Lactam-substituted dicarboxylic acids and use thereof

ABSTRACT

The present application relates to novel lactam-substituted dicarboxylic acid derivatives, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prevention of cardiovascular disorders.

The present application relates to novel lactam-substituted dicarboxylicacid derivatives, processes for their preparation, their use for thetreatment and/or prophylaxis of diseases, and their use for producingmedicaments for the treatment and/or prophylaxis of diseases, especiallyfor the treatment and/or prevention of cardiovascular disorders.

One of the most important cellular transmission systems in mammaliancells is cyclic guanosine monophosphate (cGMP). Together with nitricoxide (NO), which is released from the endothelium and transmitshormonal and mechanical signals, it forms the NO/cGMP system. Guanylatecyclases catalyze the biosynthesis of cGMP from guanosine triphosphate(GTP). The representatives of this family disclosed to date can bedivided both according to structural features and according to the typeof ligands into two groups: the particulate guanylate cyclases which canbe stimulated by natriuretic peptides, and the soluble guanylatecyclases which can be stimulated by NO. The soluble guanylate cyclasesconsist of two subunits and very probably contain one heme perheterodimer, which is part of the regulatory site. The latter is ofcentral importance for the mechanism of activation. NO is able to bindto the iron atom of heme and thus markedly increase the activity of theenzyme. Heme-free preparations cannot, by contrast, be stimulated by NO.Carbon monoxide (CO) is also able to attach to the central iron atom ofheme, but the stimulation by CO is distinctly less than that by NO.

Through the production of cGMP and the regulation, resulting therefrom,of phosphodiesterases, ion channels and protein kinases, guanylatecyclase plays a crucial part in various physiological processes, inparticular in the relaxation and proliferation of smooth muscle cells,in platelet aggregation and adhesion and in neuronal signaltransmission, and in disorders caused by an impairment of theaforementioned processes. Under pathophysiological conditions, theNO/cGMP system may be suppressed, which may lead for example to highblood pressure, platelet activation, increased cellular proliferation,endothelial dysfunction, atherosclerosis, angina pectoris, heartfailure, thromboses, stroke and myocardial infarction.

A possible way of treating such disorders which is independent of NO andaims at influencing the cGMP signaling pathway in organisms is apromising approach because of the high efficiency and few side effectswhich are to be expected.

Compounds, such as organic nitrates, whose effect is based on NO have todate been exclusively used for the therapeutic stimulation of solubleguanylate cyclase. NO is produced by bioconversion and activates solubleguanylate cyclase by attaching to the central iron atom of heme. Besidesthe side effects, the development of tolerance is one of the crucialdisadvantages of this mode of treatment.

Some substances which directly stimulate soluble guanylate cyclase, i.e.without previous release of NO, have been described in recent years,such as, for example, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole[YC-1, Wu et al., Blood 84 (1994), 4226; Mülsch et al., Brit. J.Pharmacol. 120 (1997), 681], fatty acids [Goldberg et al., J. Biol.Chem. 252 (1977), 1279], diphenyliodonium hexafluorophosphate [Pettiboneet al., Eur. J. Pharmacol. 116 (1985), 307], isoliquiritigenin [Yu etal., Brit. J. Pharmacol. 114 (1995), 1587] and various substitutedpyrazole derivatives (WO 98/16223, WO 98/16507 and WO 98/23619).

The above-described stimulators of soluble guanylate cyclase stimulatethe enzyme either directly via the heme group (carbon monoxide, nitricoxide or diphenyliodonium hexafluorophosphate) by interacting with theiron center of the heme group and a change in conformation which resultstherefrom and leads to an increase in the enzymic activity [Gerzer etal., FEBS Lett. 132 (1981), 71] or via a heme-dependent mechanism whichis independent of NO but leads to a potentiation of the stimulatingeffect of NO or CO [e.g. YC-1, Hoenicka et al., J. Mol. Med. 77 (1999)14; or the pyrazole derivatives described in WO 98/16223, WO 98/16507and WO 98/23619].

It has not been possible to confirm the stimulating effect, asserted inthe literature, of isoliquiritigenin and of fatty acids such as, forexample, of arachidonic acid, prostaglandin endoperoxides and fatty acidhydroperoxides on soluble guanylate cyclase [cf., for example, Hoenickaet al., J. Mol. Med. 77 (1999), 14].

If the heme group is removed from soluble guanylate cyclase, the enzymestill shows a detectable basal catalytic activity, i.e. cGMP is stillproduced. The remaining basal catalytic activity of the heme-free enzymecannot be stimulated by any of the aforementioned known stimulators.

Stimulation of heme-free soluble guanylate cyclase by protoporphyrin IXhas been described [Ignarro et al., Adv. Pharmacol. 26 (1994), 35].However, protoporphyrin IX can be regarded as a mimic of the NO-hemeadduct, which is why addition of protoporphyrin IX to soluble guanylatecyclase ought to lead to production of a structure of the enzymecorresponding to the heme-containing soluble guanylate cyclase which isstimulated by NO. This is also verified by the fact that the stimulatingeffect of protoporphyrin IX is increased by the NO-independent butheme-dependent stimulator YC-1 described above [Mülsch et al., NaunynSchmiedebergs Arch. Pharmacol. 355, R47].

In contrast to the above-described stimulators of soluble guanylatecyclase, the compounds of the present invention are able to activateboth the heme-containing and the heme-free form of soluble guanylatecyclase. Thus, with these novel activators, the enzyme is stimulated viaa heme-independent pathway, which is also verified by the facts that thenovel activators firstly show no synergistic effect with NO on theheme-containing enzyme, and secondly the effect of these novelactivators cannot be blocked by the heme-dependent inhibitor of solubleguanylate cyclase 1H-1,2,4-oxadiazole-(4,3-a)-quinoxalin-1-one (ODQ)[Schmidt et al., J. Clin. Invest. 116 (2006), 2552; Stasch et al.,Nature Rev. Drug Disc. 5 (2006), 755].

EP 0 341 551-A1 discloses alkenoic acid derivatives as leucotrieneantagonists for the treatment of disorders of the circulatory andrespiratory systems. WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780,WO 02/070462 and WO 02/070510 describe dicarboxylic acid and aminodicarboxylic acid derivatives as stimulators of soluble guanylatecyclase for the treatment of cardiovascular disorders. However, it hasemerged that these compounds have disadvantages in relation to theirpharmacokinetic properties, such as, in particular, a lowbioavailability and/or an only short duration of action after oraladministration.

It was therefore an object of the present invention to provide novelcompounds which act as activators of soluble guanylate cyclase but donot have the aforementioned disadvantages of the prior art compounds.

This object is achieved by the compounds described in the presentinvention. These compounds differ structurally in comparison with thecompounds of the prior art by a 3-(carboxybenzyl)- or3-(carboxyphenethyl)-5-phenylpent-4-en-1-ylbenzoic acid core structurecombined with a lactam or lactam-like side chain.

The present invention relates specifically to compounds of the generalformula (I)

in which

-   A represents a group of the formula

in which

-   -   * represents the point of attachment to group E,    -   R⁴ represents (C₁-C₆)-alkyl or phenyl,    -   x represents the number 0, 1 or 2,        -   where if the substituent R⁴ occurs twice, its meanings may            be identical or different, and    -   y represents the number 2, 3 or 4,        -   where a CH₂ group may be replaced by —O— or >N—R^(4A) in            which        -   R^(4A) is hydrogen, (C₁-C₆)-alkyl or phenyl,

-   E represents (C₂-C₆)-alkanediyl, (C₂-C₆)-alkenediyl or    (C₂-C₆)-alkynediyl, each of which may be mono- or polysubstituted by    fluorine,

-   m represents the number 1 or 2,

-   R¹, R² and R³ independently of one another represent a substituent    selected from the group consisting of halogen, (C₁-C₆)-alkyl,    trifluoromethyl, (C₁-C₆)-alkoxy, trifluoromethoxy, cyano and nitro,

-   and

-   n, o and p independently of one another each represent the number 0,    1 or 2,    -   where, if R¹, R² or R³ is present more than once, their meanings        may in each case be identical or different,        and the salts, solvates and solvates of the salts thereof.

Compounds according to the invention are the compounds of the formula(I) and the salts, solvates and solvates of the salts thereof, thecompounds which are encompassed by formula (I) and are of the formulaementioned hereinafter, and the salts, solvates and solvates of the saltsthereof, and the compounds which are encompassed by formula (I) and arementioned hereinafter as exemplary embodiments, and the salts, solvatesand solvates of the salts thereof, insofar as the compounds encompassedby formula (I) and mentioned hereinafter are not already salts, solvatesand solvates of the salts.

The compounds according to the invention may, depending on theirstructure, exist in stereoisomeric forms (enantiomers, diastereomers).The invention therefore relates to the enantiomers or diastereomers andrespective mixtures thereof. The stereoisomerically pure constituentscan be isolated in a known manner from such mixtures of enantiomersand/or diastereomers.

Where the compounds according to the invention can occur in tautomericforms, the present invention encompasses all tautomeric forms.

Salts preferred for the purposes of the present invention arephysiologically acceptable salts of the compounds according to theinvention. However, salts which are themselves unsuitable forpharmaceutical applications but can be used for example for isolating orpurifying the compounds according to the invention are also encompassed.

Physiologically acceptable salts of the compounds according to theinvention include acid addition salts of mineral acids, carboxylic acidsand sulfonic acids, e.g. salts of hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonicacid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonicacid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid,tartaric acid, malic acid, citric acid, fumaric acid, maleic acid andbenzoic acid.

Physiologically acceptable salts of the compounds according to theinvention also include salts of conventional bases such as, for exampleand preferably, alkali metal salts (e.g. sodium and potassium salts),alkaline earth metal salts (e.g. calcium and magnesium salts) andammonium salts derived from ammonia or organic amines having 1 to 16 Catoms, such as, for example and preferably, ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methyl-morpholine, arginine, lysine, ethylenediamineand N-methylpiperidine.

Solvates refer for the purposes of the invention to those forms of thecompounds according to the invention which form a complex in the solidor liquid state through coordination with solvent molecules. Hydratesare a specific form of solvates in which the coordination takes placewith water. Solvates preferred in the context of the present inventionare hydrates.

The present invention also encompasses prodrugs of the compoundsaccording to the invention. The term “prodrugs” encompasses compoundswhich themselves may be biologically active or inactive but areconverted during their residence time in the body into compoundsaccording to the invention (for example by metabolism or hydrolysis).

In the context of the present invention, the substituents have thefollowing meaning unless otherwise specified:

(C₁-C₆)-Alkyl and (C₁-C₄)-alkyl are in the context of the invention astraight-chain or branched alkyl radical having respectively 1 to 6 and1 to 4 carbon atoms. A straight-chain or branched alkyl radical having 1to 4 carbon atoms is preferred. Examples which may be preferablymentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

(C₂-C₆)-Alkanediyl and (C₂-C₄)-alkanediyl are in the context of theinvention a straight-chain or branched divalent alkyl radical havingrespectively 2 to 6 and 2 to 4 carbon atoms. A straight-chain orbranched alkanediyl radical having 2 to 4 carbon atoms is preferred.Examples which may be preferably mentioned are: ethane-1,2-diyl(1,2-ethylene), ethane-1,1-diyl, propane-1,3-diyl (1,3-propylene),propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl(1,4-butylene), butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl,pentane-1,5-diyl (1,5-pentylene), pentane-2,4-diyl,3-methylpentane-2,4-diyl and hexane-1,6-diyl (1,6-hexylene).

(C₂-C₆)-Alkenediyl and (C₂-C₄)-alkenediyl are in the context of theinvention a straight-chain or branched divalent alkenyl radical havingrespectively 2 to 6 and 2 to 4 carbon atoms and up to 2 double bonds. Astraight-chain alkenediyl radical having 2 to 4 carbon atoms and onedouble bond is preferred. Examples which may be preferably mentionedare: ethene-1,1-diyl, ethene-1,2-diyl, propene-1,1-diyl,propene-1,2-diyl, propene-1,3-diyl, but-1-ene-1,4-diyl,but-1-ene-1,3-diyl, but-2-ene-1,4-diyl, buta-1,3-diene-1,4-diyl,pent-2-ene-1,5-diyl, hex-3-ene-1,6-diyl and hexa-2,4-diene-1,6-diyl.

(C₂-C₆)-Alkynediyl and (C₂-C₄)-alkynediyl are in the context of theinvention a straight-chain or branched divalent alkynyl radical havingrespectively 2 to 6 and 2 to 4 carbon atoms and up to 2 triple bonds. Astraight-chain alkynediyl radical having 2 to 4 carbon atoms and onetriple bond is preferred. Examples which may be preferably mentionedare: ethyne-1,2-diyl, propyne-1,3-diyl, but-1-yne-1,4-diyl,but-1-yne-1,3-diyl, but-2-yne-1,4-diyl, pent-2-yne-1,5-diyl,pent-2-yne-1,4-diyl and hex-3-yne-1,6-diyl.

(C₁-C₆)-Alkoxy and (C₁-C₄)-alkoxy are in the context of the invention astraight-chain or branched alkoxy radical having respectively 1 to 6 and1 to 4 carbon atoms. A straight-chain or branched alkoxy radical having1 to 4 carbon atoms is preferred. Examples which may be preferablymentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, n-pentoxy and n-hexoxy.

(C₁-C₄)-Alkoxycarbonyl is in the context of the invention astraight-chain or branched alkoxy radical having 1 to 4 carbon atomswhich is attached via a carbonyl group. Examples which may be preferablymentioned are: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,iso-propoxycarbonyl and tert-butoxycarbonyl.

Halogen in the context of the invention includes fluorine, chlorine,bromine and iodine. Chlorine, fluorine or bromine are preferred,particularly preferably fluorine or chlorine.

If radicals in the compounds according to the invention are substituted,the radicals may, unless otherwise specified, be substituted one or moretimes. In the context of the present invention, all radicals which occurmore than once have a mutually independent meaning. Substitution by one,two or three identical or different substituents is preferred.Substitution by one substituent is very particularly preferred.

If a radical in the compounds according to the invention can bepolysubstituted by fluorine, this includes in the context of the presentinvention a perfluoro substitution.

Preference is given in the context of the present invention to compoundsof the formula (I) in which

-   A represents a group of the formula

in which

-   -   * represents the point of attachment to group E,    -   R⁴ represents (C₁-C₄)-alkyl or phenyl,    -   x represents the number 0, 1 or 2,        -   where if the substituent R⁴ occurs twice, its meanings may            be identical or different, and    -   y represents the number 2 or 3,        -   where a CH₂ group may be replaced by —O— or >N—R^(4A) in            which        -   R^(4A) represents (C₁-C₄)-alkyl or phenyl,

-   E represents (C₂-C₆)-alkanediyl or (C₂-C₆)-alkenediyl,

-   m represents the number 1 or 2,

-   R¹ represents a substituent selected from the group consisting of    fluorine, chlorine, bromine, methyl, trifluoromethyl, methoxy and    trifluoromethoxy,

-   R² and R³ each represent fluorine,

-   and

-   n, o and p independently of one another each represent the number 0    or 1,    and the salts, solvates and solvates of the salts thereof.

Particular preference is given in the context of the present inventionto compounds of the formula (I-A)

in which

-   A represents a group of the formula

-   -   in which    -   * represents the point of attachment to group E,

-   E represents 1,2-ethylene, 1,3-propylene, 1,4-butylene or    1,5-pentylene,

-   m represents the number 1 or 2,

-   and    -   R¹ represents hydrogen or fluorine,        and the salts, solvates and solvates of the salts thereof.

Very particular preference is given in the context of the presentinvention to compounds of the formula (I-A)

in which

-   A represents a group of the formula

in which

-   -   * represents the point of attachment to group E,

-   E represents 1,2-ethylene, 1,3-propylene or 1,4-butylene,

-   m represents the number 1 or 2,

-   and

-   R¹ represents hydrogen or fluorine,    and the salts, solvates and solvates of the salts thereof.

The definitions of radicals indicated specifically in the respectivecombinations or preferred combinations of radicals are replaced asdesired irrespective of the particular combinations indicated for theradicals also by definitions of radicals of other combinations.

Combinations of two or more of the abovementioned preferred ranges arevery particularly preferred.

The invention further relates to a process for preparing the compoundsof the invention of the formula (I), characterized in that compounds ofthe formula (II)

in which R², R³, m, o and p each have the meanings given above and

-   T¹ and T² are identical or different and represent    (C₁-C₄)-alkoxycarbonyl,-   are either-   [A] converted in an inert solvent in the presence of a base with a    compound of the formula (III-A)

-   -   in which A, E, R¹ and n each have the meanings given above and    -   L represents phenyl or o-, m- or p-tolyl    -   and    -   X represents halide or tosylate,    -   into compounds of the formula (IV-A)

-   -   in which A, E, R¹, R², R³, m, n, o, p, T¹ and T² each have the        meanings given above, or

-   [B] converted in an inert solvent in the presence of a base with a    compound of the formula (III-B)

-   -   in which R¹, n, L and X each have the meanings given above,    -   initially into compounds of the formula (IV-B)

-   -   in which R¹, R², R³, m, n, o, p, T¹ and T² each have the        meanings given above,    -   and these are then alkylated in an inert solvent in the presence        of a base with a compound of the formula (V)        A-E-Q  (V),    -   in which A and E have the meanings given above and    -   Q represents a leaving group, such as, for example, halogen,        tosylate or mesylate, to give compounds of the formula (IV-C)

-   -   in which A, E, R¹, R², R³, m, n, o, p, T¹ and T² each have the        meanings given above, and the resulting compounds of the formula        (IV-A) or (IV-C) are converted by hydrolysis of the ester groups        T¹ and T² into the dicarboxylic acids of the formula (I)        and the compounds of the formula (I) are separated where        appropriate by methods known to the skilled person into their        enantiomers and/or diastereomers, and/or where appropriate        reacted with the appropriate (i) solvents and/or (ii) bases or        acids to give the solvates, salts and/or solvates of the salts        thereof.

Examples of inert solvents for process steps (II)+(III-A)→(IV-A) and(II)+(III-B)→(IV-B) are ethers such as diethyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, or hydrocarbons such as benzene, toluene, xylene, pentane,hexane, heptane, cyclohexane or petroleum fractions, or mixtures ofthese solvents. Preference is given to using a mixture oftetrahydrofuran and hexane.

Suitable bases for these reaction steps are the bases customary forWittig reactions. These include in particular strong bases such as n-,sec- or tert-butyllithium, lithium diisopropylamide (LDA) or lithiumbis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassiumbis(trimethylsilyl)amide. Preference is given to n-butyllithium.

The reactions (II)+(III-A)→(IV-A) and (II)+(III-B)→(IV-B) are generallycarried out in a temperature range from −78° C. to +20° C., preferablyfrom −20° C. to +10° C.

Any cis/trans mixtures of the compound (IV-A) obtained, if appropriate,in the reaction (II)+(III-A)→(IV-A) may be separated at this stage or atthe subsequent stage of the compound (I) by customary methods, forexample by chromatography. The reaction (II)+(III-B)→(IV-B) is usuallytrans-selective.

Examples of inert solvents for process step (IV-B)+(V)→(IV-C) are etherssuch as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether, hydrocarbons such as benzene,toluene, xylene, pentane, hexane, heptane, cyclohexane or petroleumfractions, or other solvents such as acetonitrile, dimethylformamide,dimethyl sulfoxide, N,N′-dimethylpropyleneurea (DMPU) orN-methylpyrrolidone (NMP). It is also possible to employ mixtures ofsaid solvents. Preference is given to using acetonitrile,dimethylformamide, dioxane or toluene.

Suitable bases for this reaction step are in particular sodiumcarbonate, potassium carbonate or cesium carbonate, sodium hydride orpotassium hydride, lithium diisopropylamide or n-butyllithium.Preference is given to using potassium carbonate, cesium carbonate orsodium hydride.

The reaction (IV-B)+(V)→(IV-C) is generally carried out in a temperaturerange from +20° C. to +150° C., preferably from +50° C. to +120° C.

Hydrolysis of the ester groups T¹ and T² in process steps (IV-A)→(I) and(IV-C)→(I) takes place by conventional methods, by treating the estersin inert solvents with acids or bases, and with the latter convertingthe initially produced salts into the free carboxylic acids by treatmentwith acid. The ester cleavage in the case of tert-butyl esterspreferably takes place with acids.

In the case of two different groups T¹ and T², the hydrolysis may, ifappropriate, be carried out in a one-pot reaction or in two separatereaction steps.

Inert solvents suitable for these reactions are water or the organicsolvents usual for ester cleavage. These preferably include alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol ortert-butanol, or ethers such as diethyl ether, tetrahydrofuran, dioxaneor glycol dimethyl ether, or other solvents such as acetone,dichloromethane, dimethylformamide or dimethyl sulfoxide. It is alsopossible to employ mixtures of the solvents mentioned. In the case of abasic ester hydrolysis, preferably mixtures of water with dioxane,tetrahydrofuran, methanol and/or ethanol are employed. In the case ofreaction with trifluoroacetic acid, preferably dichloromethane is used,and in the case of reaction with hydrogen chloride, preferablytetrahydrofuran, diethyl ether, dioxane or water is used.

Suitable bases are the usual inorganic bases. These preferably includealkali metal or alkaline earth metal hydroxides such as, for example,sodium hydroxide, lithium hydroxide, potassium hydroxide or bariumhydroxide, or alkali metal or alkaline earth metal carbonates such assodium carbonate, potassium carbonate or calcium carbonate. Use isparticularly preferably made of sodium hydroxide, potassium hydroxide orlithium hydroxide.

Suitable acids for the ester cleavage are generally sulfuric acid,hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid,phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulfonicacid, methanesulfonic acid or trifluoromethanesulfonic acid or mixturesthereof, where appropriate with addition of water. Hydrogen chloride ortrifluoroacetic acid are preferred in the case of the tert-butyl esters,and hydrochloric acid in the case of the methyl esters.

The ester cleavage generally takes place in a temperature range from 0°C. to +100° C., preferably at +20° C. to +60° C.

The reactions mentioned can be carried out under atmospheric, elevatedor reduced pressure (e.g. from 0.5 to 5 bar). They are generally carriedout under atmospheric pressure.

The aldehydes of the formula (II) can be prepared analogously toprocesses known from the literature, for example by a double alkylationof diallyl malonate with compounds of the formulae (VI) and (VII)

in which R², R³, m, o, p, T¹ and T² each have the meanings given aboveand

-   Y¹ and Y² are identical or different and represent a leaving group,    such as, for example, halogen, mesylate or tosylate,-   to give compounds of the formula (VIII)

in which R², R³, m, o, p, T¹ and T² each have the meanings given above,subsequent ester cleavage to give compounds of the formula (IX)

in which R², R³, m, o, p, T¹ and T² each have the meanings given above,

-   and subsequent reduction of the carboxylic acid grouping (see also    Reaction Schemes 1 and 3 below).

The compounds of the formulae (III-A) and (III-B) can be obtained byprocesses customary in the literature by reacting compounds of theformula (X-A) or (X-B)

in which A, E, R¹ and n each have the meanings given above and

-   Z represents a leaving group, such as, for example, halogen or    tosylate, or represents hydroxyl,    for example with triphenylphosphine or (in the case of Z═OH)    triphenylphosphine hydrobromide (see also Reaction Scheme 5 below).

The compounds of the formulae (V), (VI), (VII), (X-A) and (X-B) arecommercially available, known from the literature or can be preparedanalogously to processes known from the literature. The compounds of theformula (X-A) can be obtained, for example, analogously to process step(IV-B)+(V)→(IV-C) by alkylating compounds of the formula (X-B) in whichZ represents hydroxyl with a compound of the formula (V) (see ReactionScheme 5).

Separation of the compounds of the invention into the correspondingenantiomers and/or diastereomers can take place where appropriate,depending on expediency, even at the stage of the compounds (IV-A),(IV-B), (IV-C) or (IX), which are then reacted further in separated formin accordance with the described process sequences. Such a fractionationof the stereoisomers can be carried out by conventional methods known tothe skilled person; chromatographic methods or separation viadiastereomeric salts are preferably used.

The preparation of the compounds of the invention can be illustrated bythe following synthesis schemes:

[Abbreviations: Ac=acetyl; BH₃×THF=borane/tetrahydrofuran complex;Bu=butyl; DMF=dimethylformamide; PCC=pyridinium chlorochromate;Ph=phenyl; Q=leaving group, e.g. halogen; THF=tetrahydrofuran].

The compounds according to the invention have valuable pharmacologicalproperties and can be used for the prevention and treatment of disordersin humans and animals.

The compounds of the present invention exhibit, as particular andsurprising feature, advantageous pharmacokinetic properties such as, forexample, an increased bioavailability and/or a prolonged duration ofaction after oral administration.

The compounds according to the invention lead to vasorelaxation, to aninhibition of platelet aggregation and to a reduction in blood pressure,and to an increase in coronary blood flow. These effects are mediated bydirect activation of soluble guanylate cyclase and an intracellularincrease in cGMP.

The compounds according to the invention can therefore be employed inmedicaments for the treatment of cardiovascular disorders such as, forexample, for the treatment of high blood pressure and heart failure,stable and unstable angina pectoris, pulmonary hypertension, peripheraland cardiac vascular disorders, arrhythmias, for the treatment ofthromboembolic disorders and ischemias such as myocardial infarction,stroke, transitory and ischemic attacks, disturbances of peripheralblood flow, prevention of restenoses as after thrombolysis therapies,percutaneous transluminal angioplasties (PTAs), percutaneoustransluminal coronary angioplasties (PTCAs), bypass and for thetreatment of arteriosclerosis, asthmatic disorders and diseases of theurogenital system such as, for example, prostate hypertrophy, erectiledysfunction, female sexual dysfunction, and incontinence, osteoporosis,glaucoma, and gastroparesis.

The compounds according to the invention can additionally be used forthe treatment of primary and secondary Raynaud's phenomenon, ofmicrocirculation impairments, claudication, peripheral and autonomicneuropathies, diabetic microangiopathies, diabetic retinopathy, diabeticulcers on the extremities, CREST syndrome, erythematosis, onychomycosisand rheumatic disorders.

The compounds according to the invention are furthermore suitable forthe treatment of respiratory distress syndromes and chronic obstructiveairway disorders (COPD), of acute and chronic renal failure and forpromoting wound healing.

The compounds described in the present invention also represent activeingredients for controlling central nervous system diseasescharacterized by disturbances of the NO/cGMP system. They are suitablein particular for improving perception, concentration, learning ormemory after cognitive impairments like those occurring in particular inassociation with situations/diseases/syndromes such as mild cognitiveimpairment, age-associated learning and memory impairments,age-associated memory losses, vascular dementia, craniocerebral trauma,stroke, dementia occurring after strokes (post stroke dementia),post-traumatic craniocerebral trauma, general concentration impairments,concentration impairments in children with learning and memory problems,Alzheimer's disease, Lewy body dementia, dementia with degeneration ofthe frontal lobes including Pick's syndrome, Parkinson's disease,progressive nuclear palsy, dementia with corticobasal degeneration,amyolateral sclerosis (ALS), Huntington's disease, multiple sclerosis,thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia,schizophrenia with dementia or Korsakoff's psychosis. They are alsosuitable for the treatment of central nervous system disorders such asstates of anxiety, tension and depression, CNS-related sexualdysfunctions and sleep disturbances, and for controlling pathologicaldisturbances of the intake of food, stimulants and addictive substances.

The compounds according to the invention are furthermore also suitablefor controlling cerebral blood flow and thus represent effective agentsfor controlling migraine. They are also suitable for the prophylaxis andcontrol of the sequalae of cerebral infarctions (Apoplexia cerebri) suchas stroke, cerebral ischemias and craniocerebral trauma. The compoundsaccording to the invention can likewise be employed for controllingstates of pain.

In addition, the compounds according to the invention have ananti-inflammatory effect and can therefore be employed asanti-inflammatory agents.

The present invention further relates to the use of the compoundsaccording to the invention for the treatment and/or prevention ofdisorders, especially of the aforementioned disorders.

The present invention further relates to the use of the compoundsaccording to the invention for producing a medicament for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders.

The present invention further relates to a method for the treatmentand/or prevention of disorders, especially of the aforementioneddisorders, by using an effective amount of at least one of the compoundsaccording to the invention.

The compounds according to the invention can be employed alone or, ifrequired, in combination with other active ingredients. The presentinvention further relates to medicaments comprising at least one of thecompounds according to the invention and one or more further activeingredients, in particular for the treatment and/or prevention of theaforementioned disorders. Examples of suitable combination activeingredients which may be preferably mentioned are:

-   -   organic nitrates and NO donors such as, for example, sodium        nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide        dinitrate, molsidomine or SIN-1, and inhaled NO;    -   compounds which inhibit the breakdown of cyclic guanosine        monophosphate (cGMP), such as, for example, inhibitors of        phosphodiesterases (PDE) 1, 2 and/or 5, in particular PDE 5        inhibitors such as sildenafil, vardenafil and tadalafil;    -   NO-independent but heme-dependent stimulators of guanylate        cyclase, such as, in particular, the compounds described in WO        00/06568, WO 00/06569, WO 02/42301 and WO 03/095451;    -   agents having antithrombotic activity, for example and        preferably from the group of platelet aggregation inhibitors, of        anticoagulants or of profibrinolytic substances;    -   active ingredients which lower blood pressure, for example and        preferably from the group of calcium antagonists, angiotensin        AII antagonists, ACE inhibitors, endothelin antagonists, renin        inhibitors, alpha-receptor blockers, beta-receptor blockers,        mineralocorticoid receptor antagonists, and of diuretics; and/or    -   active ingredients which modify lipid metabolism, for example        and preferably from the group of thyroid receptor agonists,        cholesterol synthesis inhibitors such as, for example and        preferably, HMG-CoA reductase inhibitors or squalene synthesis        inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors,        PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol        absorption inhibitors, lipase inhibitors, polymeric bile acid        adsorbents, bile acid reabsorption inhibitors and        lipoprotein (a) antagonists.

Agents having antithrombotic activity preferably mean compounds from thegroup of platelet aggregation inhibitors, of anticoagulants or ofprofibrinolytic substances.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a plateletaggregation inhibitor such as, for example and preferably, aspirin,clopidogrel, ticlopidin or dipyridamole.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thrombin inhibitorsuch as, for example and preferably, ximelagatran, melagatran,bivalirudin or clexane.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a GPIIb/IIIaantagonist such as, for example and preferably, tirofiban or abciximab.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a factor Xa inhibitorsuch as, for example and preferably, BAY 59-7939, DU-176b, fidexaban,razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982,EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 orSSR-128428.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with heparin or with a lowmolecular weight (LMW) heparin derivative.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a vitamin Kantagonist such as, for example and preferably, coumarin.

Agents which lower blood pressure preferably mean compounds from thegroup of calcium antagonists, angiotensin AII antagonists, ACEinhibitors, endothelin antagonists, renin inhibitors, alpha-receptorblockers, beta-receptor blockers, mineralocorticoid receptorantagonists, and of diuretics.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a calcium antagonistsuch as, for example and preferably, nifedipine, amlodipine, verapamilor diltiazem.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an alpha-1-receptorblocker such as, for example and preferably, prazosin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a beta-receptorblocker such as, for example and preferably, propranolol, atenolol,timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol,metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol,betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol,carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an angiotensin AIIantagonist such as, for example and preferably, losartan, candesartan,valsartan, telmisartan or embursatan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACE inhibitor suchas, for example and preferably, enalapril, captopril, lisinopril,ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an endothelinantagonist such as, for example and preferably, bosentan, darusentan,ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a renin inhibitorsuch as, for example and preferably, aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a mineralocorticoidreceptor antagonist such as, for example and preferably, spironolactoneor eplerenone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a diuretic such as,for example and preferably, furosemide.

Agents which modify lipid metabolism preferably mean compounds from thegroup of CETP inhibitors, thyroid receptor agonists, cholesterolsynthesis inhibitors such as HMG-CoA reductase inhibitors or squalenesynthesis inhibitors, of ACAT inhibitors, MTP inhibitors, PPAR-alpha,PPAR-gamma and/or PPAR-delta agonists, cholesterol absorptioninhibitors, polymeric bile acid adsorbents, bile acid reabsorptioninhibitors, lipase inhibitors and of lipoprotein (a) antagonists.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a CETP inhibitor suchas, for example and preferably, torcetrapib (CP-529 414), JJT-705 orCETP vaccine (Avant).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a thyroid receptoragonist such as, for example and preferably, D-thyroxine,3,5,3′-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214).

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an HMG-CoA reductaseinhibitor from the class of statins such as, for example and preferably,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rosuvastatin, cerivastatin or pitavastatin.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a squalene synthesisinhibitor such as, for example and preferably, BMS-188494 or TAK-475.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an ACAT inhibitorsuch as, for example and preferably, avasimibe, melinamide, pactimibe,eflucimibe or SMP-797.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with an MTP inhibitor suchas, for example and preferably, implitapide, BMS-201038, R-103757 orJTT-130.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-gamma agonistsuch as, for example and preferably, pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a PPAR-delta agonistsuch as, for example and preferably, GW 501516 or BAY 68-5042.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a cholesterolabsorption inhibitor such as, for example and preferably, ezetimibe,tiqueside or pamaqueside.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipase inhibitorsuch as, for example and preferably, orlistat.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a polymeric bile acidadsorbent such as, for example and preferably, cholestyramine,colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a bile acidreabsorption inhibitor such as, for example and preferably, ASBT (=IBAT)inhibitors such as, for example, AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

In a preferred embodiment of the invention, the compounds according tothe invention are administered in combination with a lipoprotein (a)antagonist such as, for example and preferably, gemcabene calcium(CI-1027) or nicotinic acid.

The present invention further relates to medicaments which comprise atleast one compound according to the invention, normally together withone or more inert, non-toxic, pharmaceutically suitable excipients, andto the use thereof for the aforementioned purposes.

The compounds according to the invention can act systemically and/orlocally. For this purpose, they can be administered in a suitable waysuch as, for example, by the oral, parenteral, pulmonary, nasal,sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival,optic route or as implant or stent.

The compounds according to the invention can be administered inadministration forms suitable for these administration routes.

Suitable for oral administration are administration forms which functionaccording to the prior art and deliver the compounds according to theinvention rapidly and/or in modified fashion, and which contain thecompounds according to the invention in crystalline and/or amorphizedand/or dissolved form, such as, for example, tablets (uncoated or coatedtablets, for example having enteric coatings or coatings which areinsoluble or dissolve with a delay and control the release of thecompound according to the invention), tablets which disintegrate rapidlyin the mouth, or films/wafers, films/lyophilisates, capsules (forexample hard or soft gelatin capsules), sugar-coated tablets, granules,pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can take place with avoidance of an absorptionstep (e.g. intravenous, intraarterial, intracardiac, intraspinal orintralumbar) or with inclusion of an absorption (e.g. intramuscular,subcutaneous, intracutaneous, percutaneous or intraperitoneal).Administration forms suitable for parenteral administration are, interalia, preparations for injection and infusion in the form of solutions,suspensions, emulsions, lyophilisates or sterile powders.

Suitable for the other administration routes are, for example,pharmaceutical forms for inhalation (inter alia powder inhalers,nebulizers), nasal drops, solutions or sprays; tablets for lingual,sublingual or buccal administration, films/wafers or capsules,suppositories, preparations for the ears or eyes, vaginal capsules,aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions,ointments, creams, transdermal therapeutic systems (e.g. patches), milk,pastes, foams, dusting powders, implants or stents.

Oral or parenteral administration is preferred, especially oral andintravenous administration.

The compounds according to the invention can be converted into thestated administration forms. This can take place in a manner known perse by mixing with inert, non-toxic, pharmaceutically suitableexcipients. These excipients include, inter alia, carriers (for examplemicrocrystalline cellulose, lactose, mannitol), solvents (e.g. liquidpolyethylene glycols), emulsifiers and dispersants or wetting agents(for example sodium dodecyl sulfate, polyoxysorbitan oleate), binders(for example polyvinylpyrrolidone), synthetic and natural polymers (forexample albumin), stabilizers (e.g. antioxidants such as, for example,ascorbic acid), colorants (e.g. inorganic pigments such as, for example,iron oxides) and masking flavors and/or odors.

It has generally proved advantageous to administer on parenteraladministration amounts of about 0.001 to 1 mg/kg, preferably about 0.01to 0.5 mg/kg, of body weight to achieve effective results, and on oraladministration the dosage is about 0.01 to 100 mg/kg, preferably about0.01 to 20 mg/kg, and very particularly preferably 0.1 to 10 mg/kg, ofbody weight.

It may nevertheless be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight, route ofadministration, individual response to the active ingredient, nature ofthe preparation and time or interval over which administration takesplace. Thus, it may be sufficient in some cases to make do with lessthan the aforementioned minimum amount, whereas in other cases thestated upper limit must be exceeded. It may in the event ofadministration of larger amounts be advisable to divide these into aplurality of individual doses over the day.

The following exemplary embodiments illustrate the invention. Theinvention is not restricted to the examples.

The percentage data in the following tests and examples are, unlessindicated otherwise, percentages by weight; parts are parts by weight.Solvent ratios, dilution ratios and concentration data for theliquid/liquid solutions are in each case based on volume.

A. EXAMPLES

Abbreviations:

abs. absolute

aq. aqueous

CI chemical ionization (in MS)

DCI direct chemical ionization (in MS)

DMF dimethylformamide

DMSO dimethyl sulfoxide

ee enantiomeric excess

EI electron impact ionization (in MS)

eq. equivalent(s)

ESI electrospray ionization (in MS)

Ex. Example

GC gas chromatography

h hour(s)

HPLC high pressure, high performance liquid chromatography

LC/MS coupled liquid chromatography-mass spectroscopy

min minute(s)

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

R_(f) retention index (in TLC)

RT room temperature

R_(t) retention time (in HPLC)

THF tetrahydrofuran

TLC thin-layer chromatography

UV ultraviolet spectroscopy

v/v volume to volume ratio (of a solution)

LC/MS Methods:

Method 1 (LC-MS)

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 series;UV DAD; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm;mobile phase A: 1 l of water+0.5 ml of 50% formic acid, mobile phase B:1 l of acetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90%→2.5min 30%→3.0 min 5%→4.5 min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 2 (LC-MS)

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm; mobilephase A: 1 l of water+0.5 ml of 50% formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90% A→2.5 min30% A→3.0 min 5% A→4.5 min 5% A; flow rate 0.0 min 1 ml/min→2.5 min/3.0min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 3 (LC-MS)

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100;column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm; mobile phaseA: 1 l of water+0.5 ml of 50% formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90% A→2.5 min30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 4 (LC-MS)

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column:Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm×4 mm; mobile phase A: 1 lof water+0.5 ml of 50% formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90% A→2.5 min30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 208-400 nm.

Method 5 (LC-MS)

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100;column: Thermo Hypersil GOLD 3μ 20 mm×4 mm; mobile phase A: 1 l ofwater+0.5 ml of 50% formic acid, mobile phase B: 1 l of acetonitrile+0.5ml of 50% formic acid; gradient: 0.0 min 100% A→0.2 min 100%→2.9 min 30%A→3.1 min 10% A→5.5 min 10% A; oven: 50° C.; flow rate: 0.8 ml/min; UVdetection: 210 nm.

Method 6 (LC-MS)

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Merck Chromolith SpeedROD RP-18e 100 mm×4.6 mm; mobilephase A: water+500 μl of 50% formic acid/1, mobile phase B:acetonitrile+500 μl of 50% formic acid/1; gradient: 0.0 min 10% B→7.0min 95% B→9.0 min 95% B; flow rate: 0.0 min 1.0 ml/min→7.0 min→2.0ml/min→9.0 min 2.0 ml/min; oven: 35° C.; UV detection: 210 nm.

Method 7 (LC-MS)

MS instrument type: Micromass ZQ; HPLC instrument type: HP 1100 Series;UV DAD; column: Phenomenex Gemini 3μ 30 mm×3.00 mm; mobile phase A: 1 lof water+0.5 ml of 50% formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90% A→2.5 min30% A→3.0 min 5% A→4.5 min 5% A; flow rate: 0.0 min 1 ml/min→2.5 min/3.0min/4.5 min 2 ml/min; oven: 50° C.; UV detection: 210 nm.

Method 8 (LC-MS)

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; column:Phenomenex Onyx Monolithic C18, 100 mm×3 mm; mobile phase A: 1 l ofwater+0.5 ml of 50% formic acid, mobile phase B: 1 l of acetonitrile+0.5ml of 50% formic acid; gradient: 0.0 min 90% A→2 min 65% A→4.5 min 5%A→6 min 5% A; flow rate: 2 ml/min; oven: 40° C.; UV detection: 208-400nm.

Method 9 (LC-MS)

MS instrument type: Waters ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Onyx Monolithic C18, 100 mm×3 mm; mobile phaseA: 1 l of water+0.5 ml of 50% formic acid, mobile phase B: 1 l ofacetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90% A→2 min65% A→4.5 min 5% A→6 min 5% A; flow rate: 2 ml/min; oven: 40° C.; UVdetection: 210 nm.

Method 10 (LC-MS)

MS instrument type: Micromass ZQ; HPLC instrument type: Waters Alliance2795; column: Phenomenex Synergi 2.5μ MAX-RP 100A Mercury 20 mm×4 mm;mobile phase A: 1 l of water+0.5 ml of 50% formic acid, mobile phase B:1 l of acetonitrile+0.5 ml of 50% formic acid; gradient: 0.0 min 90%A→0.1 min 90% A→3.0 min 5% A→4.0 min 5% A→4.01 min 90% A; flow rate: 2ml/min; oven: 50° C.; UV detection: 210 nm.

Method 11 (LC-MS)

Instrument: Micromass Quattro Premier with Waters UPLC Acquity; column:Thermo Hypersil GOLD 1.9μ 50 mm×1 mm; mobile phase A: 1 l of water+0.5ml of 50% formic acid, mobile phase B: 1 l of acetonitrile+0.5 ml of 50%formic acid; gradient: 0.0 min 90% A→0.1 min 90% A→1.5 min 10% A→2.2 min10% A; flow rate: 0.33 ml/min; oven: 50° C.; UV detection: 210 nm.

GC/MS Methods:

Method 1 (GC-MS)

Instrument: Micromass GCT, GC6890; column: Restek RTX-35MS, 30 m×250μm×0.25 μm; constant helium flow: 0.88 ml/min; oven: 60° C.; inlet: 250°C.; gradient: 60° C. (hold for 0.30 min), 50° C./min→120° C., 16°C./min→250° C., 30° C./min→300° C. (hold for 1.7 min).

Method 2 (GC-MS)

Instrument: Micromass GCT, GC6890; column: Restek RTX-35MS, 30 m×250μm×0.25 μm; constant helium flow: 0.88 ml/min; oven: 60° C.; inlet: 250°C.; gradient: 60° C. (hold for 0.30 min), 50° C./min→120° C., 16°C./min→250° C., 30° C./min→300° C. (hold for 8.7 min).

HPLC Methods:

Method 1 (HPLC)

Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60mm×2.1 mm, 3.5 μm; mobile phase A: 5 ml of HClO₄ (70%)/1 of water,mobile phase B: acetonitrile; gradient: 0 min 2% B→0.5 min 2% B→4.5 min90% B→9 min 90% B→9.2 min 2% B→10 min 2% B; flow rate: 0.75 ml/min;column temperature: 30° C.; UV detection: 210 nm.

Method 2 (HPLC)

Instrument: HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60mm×2.1 mm, 3.5 μm; mobile phase A: 5 ml of HClO₄ (70%)/l of water,mobile phase B: acetonitrile; gradient: 0 min 2% B→0.5 min 2% B→4.5 min90% B→15 min 90% B→15.2 min 2% B→16 min 2% B; flow rate: 0.75 ml/min;column temperature: 30° C.; UV detection: 210 nm.

Starting Compounds and Intermediates Example 1A4-Fluoro-2-(hydroxymethyl)phenol

With exclusion of oxygen, 27.1 g (159.28 mmol) of methyl5-fluoro-2-hydroxybenzoate are initially charged in 500 ml of dry THFand cooled to 0° C. With cooling, 238 ml (238 mmol) of a 1 M solution oflithium aluminum hydride in THF are then slowly added dropwise, and themixture is stirred at 0° C. for 1 hour and then at RT overnight. Afterthe reaction has gone to completion, saturated ammonium chloridesolution is added, and the mixture is taken up in dichloromethane. Theorganic phase is separated off and dried over sodium sulfate. Afterfiltration, the solvent is removed under reduced pressure. The crudeproduct is purified chromatographically on silica gel (mobile phase:cyclohexane/ethyl acetate 20:1). This gives 18.0 g (126.6 mmol, 79% oftheory) of a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 9.32 (1H, s), 7.06-7.03 (1H, m),6.86-6.81 (1H, m), 6.74-6.71 (1H, m), 5.09 (1H, t), 4.45 (2H, d).

Example 2A (5-Fluoro-2-hydroxybenzyl)(triphenyl)phosphonium bromide

18.6 g (130.87 mmol) of 4-fluoro-2-(hydroxymethyl)phenol and 42.67 g(124.32 mmol) of triphenylphosphonium hydrobromide in 186 ml ofacetonitrile are stirred under reflux for 3 h. After cooling, theprecipitate formed is filtered off and dried. This gives 58 g (124 mmol,100% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 9.82 (1H, s), 7.95-7.84 (3H, m),7.79-7.62 (12H, m), 7.02-6.91 (1H, m), 6.75-6.67 (1H, m), 6.66-6.58 (1H,m), 4.90 (2H, d).

Example 3A Methyl 4-(2-iodoethyl)benzoate

70 g (352.4 mmol) of methyl 4-(2-chloroethyl)benzoate [CAS Reg. No.65787-72-6] and 146.2 g (880.9 mmol) of potassium iodide are suspendedin 800 ml of acetonitrile and stirred under reflux for three days. Afterthe reaction has gone to completion, the reaction solution is cooled andfiltered, and the filtrate is evaporated to dryness under reducedpressure. The resulting residue is purified by flash chromatography onsilica gel (mobile phase: petroleum ether/ethyl acetate 30:1→20:1). Thisgives 101 g (348.3 mmol, 98.8% of theory) of a yellowish oil.

LC-MS (Method 7): R_(t)=2.66 min; m/z=291 (M+H)⁺.

Example 4A Diallyl bis{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate

At room temperature, 61.9 g (190.02 mmol) of cesium carbonate are addedto a solution of 10 g (54.3 mmol) of diallyl malonate and 47.25 g(purity 80%, 130.3 mmol) of methyl 4-(2-iodoethyl)-benzoate in 100 ml ofDMF, and the mixture is then stirred at room temperature overnight.After the reaction has gone to completion, the reaction solution isevaporated to dryness and the residue is taken up in 100 ml of water and100 ml of diethyl ether. The aqueous phase is extracted five times withdiethyl ether, and the combined organic phases are washed with saturatedsodium chloride solution and dried over magnesium sulfate. Afterfiltration, the solvent is removed under reduced pressure and theresidue is purified by flash chromatography on silica gel (mobile phase:petroleum ether/ethyl acetate 10:1→5:1). This gives 22.64 g (44.52 mmol,82% of theory) of a yellowish oil.

LC-MS (Method 7): R_(t)=3.14 min; m/z=509 (M+H)⁺.

Example 5A4-[4-(Methoxycarbonyl)phenyl]-2-{2-[4-(methoxycarbonyl)phenyl]ethyl}butanoicacid

At room temperature, a solution of 20.48 ml (146.9 mmol) oftriethylamine and 4.2 ml (111.29 mmol) of formic acid in 50 ml ofdioxane is added to a solution of 22.64 g (44.52 mmol) of diallylbis{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate, 0.82 g (3.12 mmol) oftriphenylphosphine and 200 mg of palladium acetate in 250 ml of dioxane.The reaction mixture is then stirred at 100° C. overnight. After thereaction has gone to completion, the reaction solution is cooled and thesolvent is removed under reduced pressure. The residue obtained is takenup in water and ethyl acetate. The aqueous phase is extracted threetimes with ethyl acetate, and the combined organic phases are washedwith saturated sodium chloride solution and dried over magnesiumsulfate. After filtration, the solvent is removed under reduced pressureand the residue is purified by flash chromatography on silica gel(mobile phase: cyclohexane/ethyl acetate 4:1). This gives 10.4 g (27.1mmol, 61% of theory) of a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.30 (1H, s), 7.86 (4H, d), 7.31 (4H,d), 3.84 (6H, s), 2.72-2.56 (4H, m), 2.29-2.18 (1H, m), 1.92-1.69 (4H,m).

LC-MS (Method 7): R_(t)=2.55 min; m/z=385 (M+H)⁺.

Example 6A Dimethyl 4,4′-[3-(hydroxymethyl)pentane-1,5-diyl]dibenzoate

At −10° C., 54.1 ml (54.1 mmol) of a 1 M borane/THF complex solution areadded dropwise to a solution of 10.4 g (27.1 mmol) of4-[4-(methoxycarbonyl)phenyl]-2-{2-[4-(methoxycarbonyl)-phenyl]ethyl}butanoicacid in 260 ml of THF. The reaction mixture is then warmed to 0° C. andstirred at this temperature for 4 h. After the reaction has gone tocompletion, saturated ammonium chloride solution is added, the reactionmixture is diluted with water and ethyl acetate and the aqueous phase isextracted twice with ethyl acetate. The combined organic phases aredried over magnesium sulfate and freed from the solvent under reducedpressure. This gives 8.73 g (23.56 mmol, 87% of theory) of a colorlessoil.

LC-MS (Method 7): R_(t)=2.62 min; m/z=371 (M+H)⁺.

Example 7A Dimethyl 4,4′-(3-formylpentane-1,5-diyl)dibenzoate

6.1 g (28.3 mmol) of pyridinium chlorochromate (PCC) are added to asolution of 8.73 g (23.6 mmol) of dimethyl4,4′-[3-(hydroxymethyl)pentane-1,5-diyl]dibenzoate in 280 ml ofdichloromethane, and the mixture is stirred at room temperature for 12h. After the reaction has gone to completion, about 10 g of silica gelare added and the solvent is removed to dryness under reduced pressure.The residue is purified by flash chromatography on silica gel (mobilephase: cyclohexane/ethyl acetate 4:1). This gives 7.08 g (19.22 mmol,81.5% of theory) of a colorless oil.

LC-MS (Method 2): R_(t)=2.61 min; m/z=369 (M+H)⁺.

Example 8A Methyl4-[(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoate

At 0° C., 2.95 ml (7.39 mmol) of a 2.5 M solution of n-butyllithium inhexane are slowly added dropwise to a solution of 1479 mg (3.2 mmol) of(5-fluoro-2-hydroxybenzyl)(triphenyl)phosphonium bromide in 40 ml ofTHF. The reaction mixture is stirred at this temperature for 45 min. At0° C., 1080 mg (2.64 mmol) of dimethyl4,4′-(3-formylpentane-1,5-diyl)dibenzoate in 10 ml of THF are metered inslowly. The reaction solution is stirred at 0° C. for 5 h, saturatedammonium chloride solution is then added and the mixture is diluted withwater and ethyl acetate. The organic phase is separated off and theaqueous phase is extracted two more times with ethyl acetate. Thecombined organic phases are dried over sodium sulfate and filtered, andthe solvent is removed to dryness. The crude product obtained ispurified by flash chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 4:1). This gives 529 mg (1.11 mmol, 42% oftheory) of a colorless oil.

LC-MS (Method 2): R_(t)=3.01 min; m/z=477 (M+H)⁺.

Example 9A Methyl4-[(4E)-5-(2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]-benzoate

At 0° C., 2.95 ml (7.39 mmol) of a 2.5 M solution of n-butyllithium inhexane are slowly added dropwise to a solution of 1422 mg (3.2 mmol) of(2-hydroxybenzyl)(triphenyl)phosphonium bromide in 40 ml of THF. Thereaction mixture is stirred at this temperature for 45 min. At 0° C.,1080 mg (2.64 mmol) of dimethyl4,4′-(3-formylpentane-1,5-diyl)dibenzoate in 10 ml of THF are thenmetered in slowly. The reaction solution is stirred at 0° C. for 5 h,saturated ammonium chloride solution is then added and the mixture isdiluted with water and ethyl acetate. The organic phase is separated offand the aqueous phase is extracted two more times with ethyl acetate.The combined organic phases are dried over sodium sulfate and filtered,and the solvent is removed to dryness. The crude product obtained ispurified by flash chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 4:1). This gives 169 mg (0.37 mmol, 14% oftheory) of a colorless oil.

LC-MS (Method 2): R_(t)=3.02 min; m/z=459 (M+H)⁺.

Example 10A Diallyl 2-(4-methoxycarbonylbenzyl)malonate

At 0° C., 14.42 g (0.36 mol) of sodium hydride are added a little at atime (caution: evolution of hydrogen) to a solution of 56.7 g (0.3 mol)of diallyl malonate in 375 ml of dioxane and 75 ml of THF. After warmingto room temperature, the mixture is stirred at 40° C. for 1 h. 111.88 g(0.6 mol) of methyl 4-chloromethylbenzoate, dissolved in 375 ml ofdioxane, are then slowly added dropwise at 40° C., and the reactionsolution is then stirred at 110° C. (bath temperature) overnight. Aftercooling to room temperature, the reaction mixture is added to 1200 ml ofwater. Here, it has to be made sure that the pH<7 (if required, a few mlof 1 M hydrochloric acid are metered in to about pH 2). The mixture isthen extracted three times with ethyl acetate, and the combined organicphases are washed with saturated sodium chloride solution and dried oversodium sulfate. After filtration, the solvent is removed to drynessunder reduced pressure. The crude product obtained is purified by flashchromatography on 3 kg of silica gel (mobile phase: petroleumether/ethyl acetate 10:1). This gives 85.4 g (0.26 mol, 85% of theory)of a colorless solid.

¹H-NMR (300 MHz, CDCl₃, δ/ppm): 7.96 (2H, d), 7.29 (2H, d), 5.91-5.74(2H, m), 5.32-5.17 (4H, m), 4.59 (4H, d), 3.93 (3H, s), 3.74 (1H, t),3.31 (2H, d).

MS (DCI, NH₃): m/z=349 (M+NH₄)⁺.

Example 11A Diallyl2-[4-(methoxycarbonyl)benzyl]-2-{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate

At room temperature, 62.66 g (192 mmol) of cesium carbonate and 46.75 g(154 mmol) of methyl 4-(2-bromoethyl)benzoate [CAS Reg. No. 136333-97-6]are added to a solution of 42.61 g (128 mmol) of diallyl2-(4-methoxycarbonylbenzyl)malonate in 450 ml of DMF. The mixture isthen stirred at room temperature overnight. After the reaction has goneto completion, the reaction solution is evaporated to dryness, and theresidue is taken up in water and extracted three times with ethylacetate. The combined organic phases are then washed with saturatedsodium chloride solution and dried over sodium sulfate. Afterfiltration, the solvent is removed to dryness under reduced pressure.The crude product obtained is purified by flash chromatography on silicagel (mobile phase: cyclohexane/ethyl acetate 13:1). This gives 41.35 g(83.6 mmol, 65% of theory) of a colorless solid.

LC-MS (Method 2): R_(t)=2.92 min; m/z=495 (M+H)⁺.

Example 12A2-[4-(Methoxycarbonyl)benzyl]-4-[4-(methoxycarbonyl)phenyl]butanoic acid

At room temperature, a solution of 37.2 ml (267 mmol) of triethylamineand 7.6 ml (202 mmol) of formic acid in 100 ml of dioxane is added to asolution of 40 g (80.9 mmol) of diallyl2-[4-(methoxycarbonyl)benzyl]-2-{2-[4-(methoxycarbonyl)phenyl]ethyl}malonate,1.49 g (5.67 mmol) of triphenylphosphine and 363 mg of palladium acetatein 500 ml of dioxane. The reaction mixture is then stirred at 110° C.overnight. After the reaction has gone to completion, the reactionsolution is cooled and the solvent is removed under reduced pressure.The residue obtained is purified by flash chromatography on silica gel(mobile phase: cyclohexane/ethyl acetate 4:1). This gives 20.98 g (56.6mmol, 70% of theory) of a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.32 (1H, s), 7.91-7.82 (4H, m),7.37-7.27 (4H, m), 3.83 (6H, s), 2.99-2.81 (2H, m), 2.77-2.56 (3H, m),1.92-1.67 (2H, m).

LC-MS (Method 7): R_(t)=2.45 min; m/z=371 (M+H)⁺.

Example 13A Dimethyl 4,4′-[2-(hydroxymethyl)butane-1,4-diyl]dibenzoate

At −10° C., 112.8 ml (112.8 mmol) of a 1 M borane/THF complex solutionare added dropwise to a solution of 20.9 g (56.4 mmol) of2-[4-(methoxycarbonyl)benzyl]-4-[4-(methoxycarbonyl)-phenyl]butanoicacid in 600 ml of THF. The reaction mixture is then warmed to 0° C. andstirred at this temperature for 4 h. After the reaction has gone tocompletion, saturated ammonium chloride solution is added, the reactionmixture is diluted with water and ethyl acetate, the phases areseparated and the aqueous phase is re-extracted twice with ethylacetate. The combined organic phases are dried over sodium sulfate and,after filtration, freed from the solvent under reduced pressure. Thisgives 20.11 g (purity 94%, 100% of theory) of a colorless solid.

LC-MS (Method 2): R_(t)=2.27 min; m/z=357 (M+H)⁺.

Example 14A Dimethyl 4,4′-(2-formylbutane-1,4-diyl)dibenzoate

13.07 g (60.6 mmol) of pyridinium chlorochromate (PCC) are added to asolution of 18.02 g (50.5 mmol) of dimethyl4,4′-[2-(hydroxymethyl)butane-1,4-diyl]dibenzoate in 350 ml ofdichloromethane, and the mixture is stirred at room temperature for 12hours. After the reaction has gone to completion, about 60 g of silicagel are added and the solvent is removed to dryness under reducedpressure. The residue is purified by flash chromatography on silica gel(mobile phase: cyclohexane/ethyl acetate 5:1→4:1). This gives 14.73 g(41.46 mmol, 82% of theory) of a colorless oil.

LC-MS (Method 7): R_(t)=2.61 min; m/z=355 (M+H)⁺.

Example 15A Methyl4-{(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}-benzoate

At 0° C., 21.65 ml (54.12 mmol) of a 2.5 M solution of n-butyllithium inhexane are slowly added dropwise to a solution of 10.84 g (23.2 mmol) of(5-fluoro-2-hydroxybenzyl)(triphenyl)-phosphonium bromide in 150 ml ofTHF, and the mixture is stirred at this temperature for 45 min. At thistemperature, 6.85 g (19.33 mmol) of dimethyl4,4′-(2-formylbutane-1,4-diyl)dibenzoate in 100 ml of THF are thenmetered in slowly. The reaction solution is stirred at 0° C. for 3 h,saturated ammonium chloride solution is then added, the mixture isdiluted with water and ethyl acetate, the organic phase is separated offand the aqueous phase is re-extracted twice with ethyl acetate. Thecombined organic phases are dried over sodium sulfate and filtered, andthe solvent is removed to dryness. The crude product obtained ispurified by flash chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 4:1). This gives 8.21 g (17.75 mmol, 76% oftheory) of a yellowish oil.

LC-MS (Method 7): R_(t)=3.14 min; m/z=463 (M+H)⁺.

Example 16A Methyl4-[(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoate

146 mg (0.91 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No.91152-30-6] and 295 mg (0.91 mmol) of anhydrous cesium carbonate areadded to a solution of 215 mg (0.45 mmol) of methyl4-[(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoatein 5 ml of dry DMF, and the mixture is then stirred at 60° C. for 12 h.The mixture is then filtered, and the filtrate is evaporated to dryness.The residue is purified by preparative HPLC. This gives 165 mg (purity93%, 0.25 mmol, 56% of theory) of a colorless oil.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.85 (4H, d), 7.32 (5H, d), 7.06-6.93(2H, m), 6.59 (1H, d), 6.27-6.15 (1H, m), 3.97 (2H, t), 3.82 (6H, s),3.39-3.32 (4H, m), 2.75-2.55 (4H, m), 2.22-2.08 (3H, m), 1.98-1.62 (8H,m).

LC-MS (Method 7): R_(t)=3.15 min; m/z=602 (M+H)⁺.

Example 17A Methyl4-[(4E)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]-phenyl}pent-4-en-1-yl]benzoate

119 mg (0.74 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No.91152-30-6] and 240 mg (0.74 mmol) of anhydrous cesium carbonate areadded to a solution of 169 mg (0.37 mmol) of methyl4-[(4E)-5-(2-hydroxyphenyl)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}pent-4-en-1-yl]benzoatein 2.5 ml of dry DMF, and the mixture is then stirred at 60° C. for 12h. The mixture is then filtered, and the filtrate is evaporated todryness. The residue is purified by preparative HPLC. This gives 169 mg(purity 94%, 0.27 mmol, 74% of theory) of a colorless oil.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 7.85 (4H, d), 7.48 (1H, d), 7.32 (4H,d), 7.20 (1H, t), 6.97 (1H, d), 6.91 (1H, t), 6.62 (1H, d), 6.18-6.06(1H, m), 3.99 (2H, t), 3.84 (6H, s), 3.36 (2H, t), 3.29 (2H, t),2.76-2.55 (4H, m), 2.21-2.07 (3H, m), 1.99-1.74 (6H, m), 1.74-1.61 (2H,m).

LC-MS (Method 7): R_(t)=3.28 min; m/z=584 (M+H)⁺.

Example 18A Methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate)

At 0° C., 21.65 ml (54.1 mmol) of a 2.5 M solution of n-butyllithium inhexane are added slowly to a solution of 10.42 g (23.2 mmol) of(2-hydroxybenzyl)(triphenyl)phosphonium bromide in 150 ml of anhydrousTHF. At this temperature, 6.85 g (19.3 mmol) of dimethyl4,4′-(2-formylbutane-1,4-diyl)dibenzoate, dissolved in 50 ml of THF, aremetered in slowly, and the mixture is stirred for 3 h. A little water isthen added, and the reaction solution is evaporated to dryness. Theresidue is taken up in ethyl acetate, washed with water and saturatedsodium chloride solution and dried over sodium sulfate. Afterfiltration, the solvent is evaporated to dryness and the crude productobtained is purified by flash chromatography on silica gel (mobilephase: cyclohexane/ethyl acetate 4:1). This gives 7.54 g (16.96 mmol,73% of theory) of a colorless solid.

LC-MS (Method 7): R_(t)=3.15 min; m/z=445 (M+H)⁺.

7.24 g (16.3 mmol) of the racemic methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoateobtained in this manner are separated further by preparative HPLC on achiral phase. This gives, in each case enantiomerically pure, 3.29 g and3.03 g, respectively, of the two E isomers as colorless solids (seeExamples 19A and 20A).

Example 19A Methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(enantiomer 1)

Method for the Separation of Enantiomers:

Column: Daicel Chiralpak AD-H 250 mm×20 mm; mobile phase:isohexane/isopropanol 65:35 (v/v); flow rate: 15 ml/min; UV detection:220 nm; temperature: 30° C.

R_(t) 9.07 min; purity>99%; >99% ee

Yield: 3.29 g

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 9.44 (1H, s), 7.85 (4H, t), 7.31 (5H,d), 7.01 (1H, t), 6.78 (1H, d), 6.74 (1H, t), 6.46 (1H, d), 6.12-6.02(1H, m), 3.83 (3H, s), 3.81 (3H, s), 2.92-2.82 (1H, m), 2.81-2.68 (2H,m), 2.68-2.56 (1H, m), 2.55-2.44 (1H, m), 1.84-1.73 (1H, m), 1.73-1.61(1H, m).

LC-MS (Method 2): R_(t)=2.88 min; MS (ESIpos): m/z=445 (M+H)⁺.

Example 20A Methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(enantiomer 2)

Method for the Separation of Enantiomers: see Example 19A.

R_(t) 10.29 min; purity>99%; >99% ee

Yield: 3.03 g

¹H-NMR and LC-MS: see Example 19A.

Example 21A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate(enantiomer 1)

2.33 g (14.4 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No.91152-30-6] and 4.69 g (14.4 mmol) of anhydrous cesium carbonate areadded to a solution of 3.2 g (7.2 mmol) of methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(enantiomer 1, Example 19A) in 50 ml of dry dioxane, and the mixture isthen stirred at 60° C. for 12 h. The mixture is then filtered, and thefiltrate is evaporated to dryness. The crude product obtained ispurified by flash chromatography on silica gel (mobile phase:cyclohexane/ethyl acetate 10:1→2:1→1:1). This gives 2.98 g (5.23 mmol,72% of theory) of a colorless oil.

LC-MS (Method 7): R_(t)=3.03 min; m/z=570 (M+H)⁺.

Example 22A Methyl4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(enantiomer 1)

1.69 g (8.37 mmol) of 1,3-dibromopropane, 180 mg (0.56 mmol) oftetrabutylammonium bromide and 3.85 g (27.9 mmol) of anhydrous potassiumcarbonate are added to a solution of 1.24 g (2.79 mmol) of methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(enantiomer 1, Example 19A) in 23 ml of dry toluene, and the mixture isthen stirred at 110° C. for 24 h. Another 1.69 g (8.37 mmol) of1,3-dibromopropane are then added, and the mixture is stirred at 110° C.for a further 24 h. The mixture is then filtered through kieselguhr, andthe filtrate is evaporated to dryness. The crude product obtained ispurified by flash chromatography on silica gel (mobile phase:dichloromethane). This gives 0.650 g (1.15 mmol, 41.2% of theory) of acolorless oil.

LC-MS (Method 9): R_(t)=4.75 min; m/z=565 (M+H)⁺.

Example 23A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate(enantiomer 1)

A solution of 0.175 g (1.73 mmol) of morpholin-3-one [CAS Reg. No.109-11-5] is initially charged in 6 ml of dry DMF, and 71 mg (1.78 mmol)of sodium hydride (60% in paraffin oil) are added. The mixture isstirred at room temperature for 45 min. The reaction solution is thencooled to 0° C., and a solution of 0.28 g (0.495 mmol) of methyl4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(Example 22A) in 3 ml of dry DMF is added. The mixture is stirred atroom temperature for 1 h. The reaction solution is then carefully pouredinto 50 ml of ice-cold 10% strength ammonium chloride solution. Themixture is extracted twice with dichloromethane. The combined organicphases are dried over sodium sulfate, filtered and concentrated. Thisgives 0.29 g (0.495 mmol, 100% of theory) of a colorless oil which isreacted without further purification.

LC-MS (Method 7): R_(t)=3.15 min; m/z=586 (M+H)⁺.

Example 24A Methyl4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate)

0.27 g (1.35 mmol) of 1,3-dibromopropane, 29 mg (0.089 mmol) oftetrabutylammonium bromide and 0.62 g (4.5 mmol) of anhydrous potassiumcarbonate are added to a solution of 0.2 g (0.45 mmol) of methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate, Example 18A) in 4 ml of dry toluene, and the mixture is thenstirred at 110° C. for a further 24 h. Another 0.27 g (1.35 mmol) of1,3-dibromopropane are then added, and the mixture is stirred at 110° C.for a further 24 h. The mixture is then filtered through kieselguhr, andthe filtrate is evaporated to dryness. The crude product obtained ispurified by flash chromatography on silica gel (mobile phase:dichloromethane). This gives 0.155 g (0.274 mmol, 60.9% of theory) of acolorless oil.

LC-MS (Method 2): R_(t)=5.64 min; m/z=565 (M+H)⁺.

Example 25A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate(racemate)

A solution of 0.124 g (1.42 mmol) of 1,3-oxazolidin-2-one is initiallycharged in 3.5 ml of dry DMF, and 58.6 mg (1.46 mmol) of sodium hydride(60% in paraffin oil) are added. The mixture is stirred at roomtemperature for 45 min. The reaction solution is then cooled to 0° C.,and a solution of 230 mg (0.407 mmol) of methyl4-{(4E)-5-[2-(3-bromopropoxy)phenyl]-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoate(Example 24A) in 3 ml of dry DMF is added. The mixture is stirred atroom temperature for 1 h. The reaction solution is then carefully pouredinto 50 ml of ice-cold 10% strength ammonium chloride solution. Themixture is extracted twice with dichloromethane. The combined organicphases are dried over sodium sulfate, filtered and concentrated. Thisgives 0.13 g (0.227 mmol, 55.9% of theory) of a colorless oil.

LC-MS (Method 2): R_(t)=2.94 min; m/z=572 (M+H)⁺.

130 mg (0.227 mmol) of the racemic methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)propoxy]phenyl}pent-4-en-1-yl]benzoateobtained in this manner are separated further by preparative HPLC on achiral phase. This gives, enantiomerically pure, in each case 35 mg ofthe two E isomers as colorless solids (see Examples 26A and 27A).

Example 26A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate(enantiomer 1)

Method for the Separation of Enantiomers:

Column: Daicel Chiralpak AD-H 250 mm×20 mm; mobile phase: isohexane(with 1% water and 0.2% acetic acid)/isopropanol 70:30 (v/v); flow rate:15 ml/min; UV detection: 220 nm; temperature: 25° C.

R_(t) 7.31 min; purity 98%; >98.5% ee

Yield: 35 mg.

Example 27A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate(enantiomer 2)

Method for the Separation of Enantiomers: see Example 26A.

R_(t) 8.29 min; purity 98%; >98.5% ee

Yield: 35 mg.

Example 28A Methyl4-{(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate)

0.10 g (0.622 mmol) of 1-(3-chloropropyl)pyrrolidin-2-one [CAS Reg. No.91152-30-6] and 0.338 g (1.04 mmol) of anhydrous cesium carbonate areadded to a solution of 0.3 g (0.52 mmol) of methyl4-{(4E)-5-(5-fluoro-2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}-benzoate(racemate) in 10 ml of dry dioxane/isopropanol (2:1 v/v), and themixture is then stirred at 60° C. for 18 h. The mixture is thenfiltered, and the filtrate is evaporated to dryness. The crude productobtained is purified by preparative HPLC. This gives 0.13 g (0.22 mmol,42.7% of theory) of a colorless oil.

60 mg (0.102 mmol) of the racemic methyl4-{(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)-propoxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoateobtained in this manner are separated further by preparative HPLC on achiral phase. This gives, in each case enantiomerically pure, 12.0 mgand 10.0 mg, respectively, of the two E isomers as colorless solids (seeExamples 29A and 30A).

Example 29A Methyl4-{(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoate(enantiomer 1)

Method for the Separation of Enantiomers:

Column: Daicel Chiralpak AD-H 250 mm×20 mm; mobile phase:isohexane/isopropanol 55:45 (v/v); flow rate: 15 ml/min; UV detection:220 nm; temperature: 35° C.

R_(t) 10.31 min; purity>98%; >98.0% ee

Yield: 12 mg.

Example 30A Methyl4-{(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoate(enantiomer 2)

Method for the Separation of Enantiomers: see Example 29A.

R_(t) 10.93 min; purity>98%; >98.0% ee

Yield: 10 mg.

Example 31A Methyl4-{(4E)-5-[2-(4-chlorobutoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate)

1.54 g (9.0 mmol) of 1-bromo-4-chlorobutane [CAS Reg. No. 6940-78-9] and7.33 g (22.5 mmol) of anhydrous cesium carbonate are added to a solutionof 1.0 g (2.25 mmol) of methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 18A) in 15 ml of dry toluene, and the mixture is thenstirred at 60° C. for 18 h. The mixture is then filtered, and thefiltrate is evaporated to dryness. The crude product obtained is takenup in ethyl acetate and washed twice with saturated sodium bicarbonatesolution, and the organic phase dried over sodium sulfate andconcentrated. The crude product is then purified by flash chromatographyon silica gel (mobile phase: dichloromethane). This gives 0.850 g (1.59mmol, 70.6% of theory) of a colorless oil.

LC-MS (Method 1): R_(t)=3.37 min; m/z=535 (M+H)⁺.

Example 32A Methyl4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate)

1.84 g (9.9 mmol) of 1-bromo-5-chloropentane [CAS Reg. No. 586-78-7] and6.45 g (19.8 mmol) of anhydrous cesium carbonate are added to a solutionof 1.1 g (2.47 mmol) of methyl4-{(4E)-5-(2-hydroxyphenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 18A) in 16.5 ml of dry toluene, and the mixture isthen stirred at 60° C. for 18 h. The mixture is then filtered, and thefiltrate is evaporated to dryness. The crude product obtained is takenup in ethyl acetate and washed twice with saturated sodium bicarbonatesolution, and the organic phase is dried over sodium sulfate andconcentrated. The crude product is then purified by flash chromatographyon silica gel (mobile phase: dichloromethane). This gives 1.00 g (1.82mmol, 73.6% of theory) of a colorless oil.

LC-MS (Method 10): R_(t)=3.08 min; m/z=549 (M+H)⁺.

Example 33A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(2-oxo-1,3-oxazolidin-3-yl)pentyl]oxy}-phenyl)pent-4-en-1-yl]benzoate(racemate)

A solution of 16.7 mg (0.19 mmol) of 2-oxazolidinone [CAS Reg. No.497-25-6] is initially charged in 1.0 ml of dry DMF, and 7.9 mg (0.196mmol) of sodium hydride (60% in paraffin oil) are added. The mixture isstirred at room temperature for 45 min. The reaction solution is thencooled to 0° C. and a solution of 30 mg (0.055 mmol) of methyl4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 32A) in 0.5 ml of dry DMF is added. The mixture isstirred at room temperature for 1.5 h. The reaction solution is thencarefully poured into 5 ml of ice-cold 10% strength ammonium chloridesolution. The mixture is extracted twice with dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered andconcentrated. This gives 25 mg (0.042 mmol, 76% of theory) of acolorless oil which is reacted without further purification.

LC-MS (Method 11): R_(t)=1.62 min; m/z=600 (M+H)⁺.

Example 34A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(2-methyl-3-oxomorpholin-4-yl)pentyl]-oxy}phenyl)pent-4-en-1-yl]benzoate(diastereomer mixture)

A solution of 66 mg (0.57 mmol) of 2-methylmorpholin-3-one [CAS Reg. No.100636-23-5] is initially charged in 4.5 ml of dry DMF, and 23.6 mg(0.196 mmol) of sodium hydride (60% in paraffin oil) are added. Themixture is stirred at room temperature for 45 min. The reaction solutionis then cooled to 0° C. and a solution of 90 mg (0.163 mmol) of methyl4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 32A) in 1.5 ml of dry DMF is added. The mixture isstirred at room temperature for 1.5 h. The reaction solution is thencarefully poured into 15 ml of ice-cold 10% strength ammonium chloridesolution. The mixture is extracted twice with dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered andconcentrated. This gives 103 mg (0.57 mmol, 100% of theory) of acolorless oil which is reacted without further purification.

LC-MS (Method 11): R_(t)=1.65 min; m/z=628 (M+H)⁺.

Example 35A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)pentyl]oxy}phenyl)pent-4-en-1-yl]benzoate(racemate)

A solution of 36.4 mg (0.319 mmol) of 1-methyltetrahydropyrimidin-2-one[CAS Reg. No. 10166-54-8] is initially charged in 1.5 ml of dry DMF, and13.1 mg (0.328 mmol) of sodium hydride (60% in paraffin oil) are added.The mixture is stirred at room temperature for 45 min. The reactionsolution is then cooled to 0° C. and a solution of 50 mg (0.091 mmol) ofmethyl4-{(4E)-5-{2-[(5-chloropentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 32A) in 1.5 ml of dry DMF is added. This is followedby the addition of 1.5 mg (0.9 μmol) of potassium iodide. The mixture isstirred at room temperature for 1.5 h. The reaction solution is thencarefully poured into 15 ml of ice-cold 10% strength ammonium chloridesolution. The mixture is extracted twice with dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered andconcentrated. This gives 47 mg (0.075 mmol, 82% of theory) of acolorless oil which is reacted without further purification.

LC-MS (Method 11): R_(t)=1.66 min; m/z=627 (M+H)⁺.

Example 36A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[4-(2-oxopyrrolidin-1-yl)butoxy]phenyl}pent-4-en-1-yl]benzoate(racemate)

A solution of 16.7 mg (0.196 mmol) of pyrrolidin-2-one [CAS Reg. No.616-45-5] are initially charged in 1.0 ml of dry DMF, and 8 mg (0.201mmol) of sodium hydride (60% in paraffin oil) are added. The mixture isstirred at room temperature for 45 min. The reaction solution is thencooled to 0° C. and a solution of 30 mg (0.056 mmol) of methyl4-{(4E)-5-[2-(4-chlorobutoxy)phenyl]-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 31A) in 0.5 ml of dry DMF is added. The mixture isstirred at room temperature for 1.5 h. The reaction solution is thencarefully poured into 15 ml of ice-cold 10% strength ammonium chloridesolution. The mixture is extracted twice with dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered andconcentrated. This gives 19 mg (32.5 μmol, 58% of theory) of a colorlessoil which is reacted without further purification.

LC-MS (Method 11): R_(t)=1.62 min; m/z=584 (M+H)⁺.

Example 37A Methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[2-(2-oxo-1,3-oxazolidin-3-yl)ethoxy]-phenyl}pent-4-en-1-yl]benzoate(racemate)

A solution of 82.0 mg (0.288 mmol) of 2-(2-oxo-1,3-oxazolidin-3-yl)ethyl4-methylbenzenesulfonate [CAS Reg. No. 159974-55-7] is initially chargedin 1.5 ml of dry toluene, and 187 mg (0.576 mmol) of cesium carbonateare added. 32 mg (0.072 mmol) of methyl4-{(4E)-5-(2-hydroxy-phenyl)-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 18A) are then added. The reaction mixture is stirredat 60° C. for 18 h and then carefully poured into 15 ml of ice-cold 10%strength ammonium chloride solution. The mixture is extracted twice withethyl acetate. The combined organic phases are dried over sodiumsulfate, filtered and concentrated. This gives 39 mg (0.070 mmol, 97% oftheory) of a colorless oil which is reacted without further purification

LC-MS (Method 1): R_(t)=2.98 min; m/z=558 (M+H)⁺.

Exemplary Embodiments Example 14-[(4E)-3-[2-(4-Carboxyphenyl)ethyl]-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-pent-4-en-1-yl]benzoicacid

18 mg (0.75 mmol) of lithium hydroxide are added to a solution of 150 mg(0.25 mmol) of methyl4-[(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-{2-[4-(methoxycarbonyl)-phenyl]ethyl}pent-4-en-1-yl]benzoatein 10 ml of THF and 10 ml of water, and the mixture is stirred at 50° C.for 12 h. The mixture is then adjusted to pH 2 using 1 M hydrochloricacid and concentrated. The residue obtained is purified directly bypreparative HPLC. This gives 130 mg (content 96%, 0.22 mmol, 87% oftheory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.78 (2H, broad), 7.84 (4H, d), 7.36(1H, d), 7.30 (4H, d), 7.05-6.92 (2H, m), 6.61 (1H, d), 6.28-6.16 (1H,m), 3.98 (2H, t), 3.39-3.22 (4H, m), 2.75-2.55 (4H, m), 2.22-2.10 (3H,m), 1.98-1.75 (6H, m), 1.75-1.61 (2H, m).

LC-MS (Method 2): R_(t)=2.39 min; m/z=574 (M+H)⁺.

Example 24-[(4E)-3-[2-(4-Carboxyphenyl)ethyl]-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}pent-4-en-1-yl]benzoicacid

18.5 mg (0.75 mmol) of lithium hydroxide are added to a solution of 150mg (0.26 mmol) of methyl4-[(4E)-3-{2-[4-(methoxycarbonyl)phenyl]ethyl}-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]-phenyl}pent-4-en-1-yl]benzoatein 10 ml of THF and 10 ml of water, and the mixture is stirred at 50° C.for 12 h. The mixture is then adjusted to pH 2 using 1 M hydrochloricacid and concentrated. The residue obtained is purified directly bypreparative HPLC. This gives 104 mg (content 97%, 0.18 mmol, 71% oftheory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.78 (2H, broad), 7.83 (4H, d), 7.49(1H, d), 7.32 (4H, d), 7.21 (1H, t), 6.97 (1H, d), 6.92 (1H, d), 6.64(1H, d), 6.18-6.08 (1H, m), 4.00 (2H, t), 3.41-3.22 (4H, m), 2.75-2.55(4H, m), 2.22-2.10 (3H, m), 1.99-1.74 (6H, m), 1.74-1.61 (2H, m).

LC-MS (Method 2): R_(t)=2.41 min; m/z=556 (M+H)⁺.

Example 34-[(4E)-3-(4-Carboxybenzyl)-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}pent-4-en-1-yl]-benzoicacid (enantiomer 1)

492 mg (20.5 mmol) of lithium hydroxide are added to a solution of 3.90g (6.8 mmol) of methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}pent-4-en-1-yl]benzoate(Example 21A) in 20 ml of THF and 20 ml of water, and the mixture isstirred at 50° C. for 12 h. The mixture is then cooled and extractedthree times with ethyl acetate. The aqueous phase is then adjusted to pH2 using 1 M hydrochloric acid and extracted three times with ethylacetate. The latter organic phases are combined, washed with water andsaturated sodium chloride solution and dried over sodium sulfate. Afterfiltration, the solvent is removed to dryness. This gives 2.75 g(content 98%, 4.98 mmol, 73% of theory) of the title compound as acolorless solid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.69 (2H, broad), 7.89-7.76 (4H, m),7.41 (1H, d), 7.29 (4H, d), 7.18 (1H, t), 6.95-6.84 (2H, m), 6.45 (1H,d), 6.19-6.06 (1H, m), 3.98 (2H, m), 3.40-3.19 (4H, m), 2.95-2.82 (1H,m), 2.81-2.69 (2H, m), 2.68-2.57 (1H, m), 2.56-2.45 (1H, m), 2.21-2.11(2H, m), 1.95-1.75 (5H, m), 1.76-1.61 (1H, m).

LC-MS (Method 7): R_(t)=2.56 min; m/z=542 (M+H)⁺.

Example 44-[(4E)-3-(4-Carboxybenzyl)-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}pent-4-en-1-yl]-benzoicacid (enantiomer 1)

66.6 mg (1.59 mmol) of lithium hydroxide monohydrate are added to asolution of 0.31 g (0.53 mmol) of methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-pent-4-en-1-yl]benzoate(Example 23A) in 2 ml of THF and 2 ml of water, and the mixture isstirred at room temperature for 18 h. The mixture is then adjusted to pH2 using 1 M hydrochloric acid and extracted twice with ethyl acetate.The combined organic phases are dried over sodium sulfate. Afterfiltration, the solvent is removed to dryness and the crude product ispurified by preparative HPLC. This gives 89.5 mg (0.16 mmol, 30.3% oftheory) of the title compound as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.76 (2H, broad), 7.85-7.80 (4H, m),7.40-7.38 (1H, m), 7.30-7.28 (4H, d), 7.19-7.15 (1H, m), 6.93-6.87 (2H,m), 6.49-6.45 (1H, d), 6.16-6.09 (1H, m), 4.00 (2H, s), 3.97-3.91 (2H,m), 3.79-3.76 (2H, t), 3.46-3.40 (2H, m), 3.30-3.27 (2H, m) 2.90-2.86(1H, m) 2.79-2.59 (3H, m), 2.51-2.49 (1H, m), 1.96-1.88 (2H, m),1.79-1.67 (2H, m).

LC-MS (Method 2): R_(t)=2.24 min; m/z=558 (M+H)⁺.

Example 54-[(4E)-3-(4-Carboxybenzyl)-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)propoxy]phenyl}pent-4-en-1-yl]-benzoicacid (enantiomer 1)

81.5 mg (1.94 mmol) of lithium hydroxide monohydrate are added to asolution of 370 mg (0.647 mmol) of methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(2-oxo-1,3-oxazolidin-3-yl)-propoxy]phenyl}pent-4-en-1-yl]benzoate(Example 26A) in 2 ml of THF and 2 ml of water, and the mixture isstirred at room temperature for 18 h. The mixture is then adjusted to pH2 using 1 M hydrochloric acid and extracted twice with ethyl acetate.The combined organic phases are dried over sodium sulfate. Afterfiltration, the solvent is removed to dryness and the crude product ispurified by preparative HPLC. This gives 114 mg (0.210 mmol, 32.4% oftheory) of the title compound as a colorless solid.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.75 (2H, broad), 7.85-7.80 (4H, m),7.40-7.38 (1H, m), 7.30-7.28 (4H, d), 7.19-7.15 (1H, m), 6.94-6.87 (2H,m), 6.50-6.45 (1H, d), 6.15-6.09 (1H, m), 4.23-4.20 (2H, t), 4.00-3.91(2H, m), 3.51-3.47 (2H, t), 3.31-3.25 (2H, m), 2.90-2.86 (1H, m)2.79-2.59 (3H, m), 2.51-2.50 (1H, m), 1.95-1.88 (2H, m), 1.79-1.68 (2H,m).

LC-MS (Method 2): R_(t)=2.24 min; m/z=558 (M+H)⁺.

Example 64-[(4E)-3-(4-Carboxybenzyl)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}pent-4-en-1-yl]benzoicacid (enantiomer 1)

2.57 mg (61.3 mmol) of lithium hydroxide monohydrate are added to asolution of 12 mg (10.4 μmol) of methyl4-{(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoate(Example 29A) in 0.3 ml of THF and 0.3 ml of water, and the mixture isstirred at room temperature for 16 h. The mixture is then adjusted to pH2 using 1 M hydrochloric acid and extracted twice with ethyl acetate.The combined organic phases are dried over sodium sulfate, filtered andconcentrated. The residue obtained is purified by preparative HPLC. Thisgives 5.0 mg (8.93 μmol, 43.8% of theory) of the title compound.

LC-MS (Method 9): R_(t)=3.57 min; m/z=560 (M+H)⁺.

Example 74-[(4E)-3-(4-Carboxybenzyl)-5-(2-{[5-(2-oxopiperidin-1-yl)pentyl]oxy}phenyl)pent-4-en-1-yl]-benzoicacid (racemate)

A solution of 19.0 mg (0.191 mmol) of 2-piperidinone [CAS Reg. No.675-20-7] is initially charged in 1.0 ml of dry DMF, and 7.9 mg (0.197mmol) of sodium hydride (60% in paraffin oil) are added. The mixture isstirred at room temperature for 45 min. The reaction solution is thencooled to 0° C., and a solution of 30 mg (0.056 mmol) of methyl4-{(4E)-5-{2-[(5-chloro-pentyl)oxy]phenyl}-3-[4-(methoxycarbonyl)benzyl]pent-4-en-1-yl}benzoate(racemate; Example 32A) in 1.5 ml of dry DMF is added. The mixture isstirred at room temperature for 1.5 h. The reaction solution is thencarefully poured into 15 ml of ice-cold 10% strength ammonium chloridesolution. The mixture is extracted twice with dichloromethane. Thecombined organic phases are dried over sodium sulfate, filtered andconcentrated. The residue obtained is purified by preparative HPLC. Thisgives 1.9 mg (3.25 μmol, 6.0% of theory) of the title compound.

LC-MS (Method 1): R_(t)=2.62 min; m/z=584 (M+H)⁺.

Example 84-[(4E)-3-(4-Carboxybenzyl)-5-(2-{[5-(2-oxo-1,3-oxazolidin-3-yl)pentyl]oxy}phenyl)pent-4-en-1-yl]benzoicacid (racemate)

8.75 mg (208 mmol) of lithium hydroxide monohydrate are added to asolution of 25 mg (41.7 μmol) of methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(2-oxo-1,3-oxazolidin-3-yl)-pentyl]oxy}phenyl)pent-4-en-1-yl]benzoate(Example 33A) in 0.5 ml of THF and 0.5 ml of water, and the mixture isstirred at room temperature for 16 h. The mixture is then adjusted to pH2 using 1 M hydrochloric acid and extracted twice with ethyl acetate.The combined organic phases are dried over sodium sulfate, filtered andconcentrated. The residue obtained is purified by preparative HPLC. Thisgives 1.5 mg (2.62 μmol, 6.3% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.9-12.6 (2H, broad), 7.85-7.80 (4H,m), 7.40-7.38 (1H, m), 7.30-7.27 (4H, d), 7.18-7.15 (1H, m), 6.94-6.86(2H, m), 6.46-6.42 (1H, d), 6.13-6.07 (1H, m), 4.23-4.19 (2H, t),3.97-3.87 (2H, m), 3.49-3.45 (2H, t), 3.13-3.10 (2H, m), 2.90-2.86 (1H,m), 2.79-2.70 (3H, m), 2.69-2.60 (1H, m), 1.85-1.75 (1H, m), 1.74-1.67(3H, m), 1.55-1.47 (2H, m), 1.40-1.34 (2H, m).

LC-MS (Method 1): R_(t)=2.55 min; m/z=572 (M+H)⁺.

Example 94-[(4E)-3-(4-Carboxybenzyl)-5-(2-[5-(2-methyl-3-oxomorpholin-4-yl)pentyl]oxy1-phenyl)pent-4-en-1-yl]benzoic acid (mixture of diastereomers)

33.6 mg (800 μmol) of lithium hydroxide monohydrate are added to asolution of 100.4 mg (160 μmol) of methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(2-methyl-3-oxomorpholin-4-yl)pentyl]oxy}phenyl)pent-4-en-1-yl]benzoate(Example 34A) in 1.0 ml of THF and 1.0 ml of 2 M aqueous sodiumhydroxide solution, and the mixture is stirred at room temperature for16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acidand extracted twice with ethyl acetate. The combined organic phases aredried over sodium sulfate, filtered and concentrated. The residueobtained is purified by preparative HPLC. This gives 17.7 mg (29.5 μmol,18.5% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.77 (2H, broad), 7.85-7.80 (4H, m),7.39-7.37 (1H, m), 7.30-7.28 (4H, d), 7.18-7.15 (1H, m), 6.94-6.85 (2H,m), 6.46-6.42 (1H, d), 6.13-6.07 (1H, m), 4.07-4.04 (1H, m), 3.92-3.87(3H, m), 3.69-3.64 (1H, m), 3.43-3.25 (4H, m), 3.17-3.14 (1H, m),2.90-2.85 (1H, m), 2.78-2.60 (3H, m), 1.80 (1H, m), 1.72-1.69 (3H, m),1.51-1.49 (2H, m), 1.37-1.33 (2H, m), 1.26-1.24 (3H, m).

LC-MS (Method 10): R_(t)=2.11 min; m/z=600 (M+H)⁺.

Example 104-[(4E)-3-(4-Carboxybenzyl)-5-(2-{[5-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)pentyl]oxy}-phenyl)pent-4-en-1-yl]benzoicacid (racemate)

31.5 mg (750 μmol) of lithium hydroxide monohydrate are added to asolution of 47 mg (160 μmol) of methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-(2-{[5-(3-methyl-2-oxotetrahydro-pyrimidin-1(2H)-yl)pentyl]oxy}phenyl)pent-4-en-1-yl]benzoate(Example 35A) in 1.0 ml of THF and 1.0 ml of 1 M aqueous sodiumhydroxide solution, and the mixture is stirred at room temperature for16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acidand extracted twice with ethyl acetate. The combined organic phases aredried over sodium sulfate, filtered and concentrated. The residueobtained is purified by preparative HPLC. This gives 4.2 mg (7.0 μmol,9.4% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.78 (2H, broad), 7.85-7.80 (4H, m),7.52-7.49 (1H, m), 7.30-7.28 (4H, d), 7.18-7.15 (1H, m), 6.94-6.85 (2H,m), 6.46-6.42 (1H, d), 6.13-6.07 (1H, m), 3.92-3.91 (2H, m), 3.17-3.11(6H, m), 2.88-2.84 (1H, m), 2.74 (3H, s), 2.75-2.56 (3H, m), 2.33 (1H,m), 1.82-1.78 (3H, m), 1.71-1.67 (3H, m), 1.44-1.42 (2H, m), 1.34-1.32(2H, m).

LC-MS (Method 10): R_(t)=2.11 min; m/z=599 (M+H)⁺.

Example 114-[(4E)-3-(4-Carboxybenzyl)-5-{2-[4-(2-oxopyrrolidin-1-yl)butoxy]phenyl}pent-4-en-1-yl]benzoicacid (racemate)

13.7 mg (325 μmol) of lithium hydroxide monohydrate are added to asolution of 19 mg (32.5 μmol) of methyl4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[4-(2-oxopyrrolidin-1-yl)butoxy]-phenyl}pent-4-en-1-yl]benzoate(Example 36A) in 0.5 ml of dioxane and 0.5 ml of 2 M aqueous sodiumhydroxide solution, and the mixture is stirred at room temperature for16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acidand extracted twice with ethyl acetate. The combined organic phases aredried over sodium sulfate, filtered and concentrated. The residueobtained is purified by preparative HPLC. This gives 1.8 mg (3.2 μmol,10.0% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 13.0-12.5 (2H, broad), 7.85-7.80 (4H,m), 7.40-7.38 (1H, m), 7.29-7.27 (4H, d), 7.18-7.14 (1H, m), 6.93-6.86(2H, m), 6.47-6.43 (1H, d), 6.14-6.07 (1H, m), 3.94-3.92 (2H, m),3.30-3.15 (3H, m), 3.02-2.99 (2H, m), 2.90-2.85 (1H, m), 2.80-2.60 (3H,m), 2.16-2.12 (1H, m), 1.85-1.78 (2H, m), 1.68-1.55 (7H, m).

LC-MS (Method 10): R_(t)=2.00 min; m/z=556 (M+H)⁺.

Example 124-[(4E)-3-(4-Carboxybenzyl)-5-{2-[2-(2-oxo-1,3-oxazolidin-3-yl)ethoxy]phenyl}pent-4-en-1-yl]-benzoicacid (racemate)

44.1 mg (1.05 mmol) of lithium hydroxide monohydrate are added to asolution of 39 mg (70 μmol) of methyl4[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[2-(2-oxo-1,3-oxazolidin-3-yl)ethoxy]phenyl}pent-4-en-1-yl]benzoate(Example 37A) in 0.5 ml of THF and 0.5 ml of water, and the mixture isstirred at room temperature for 16 h. The mixture is then adjusted to pH2 using 1 M hydrochloric acid and extracted twice with ethyl acetate.The combined organic phases are dried over sodium sulfate, filtered andconcentrated. The residue obtained is purified by preparative HPLC. Thisgives 5.3 mg (10 μmol, 14.3% of theory) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆, δ/ppm): 12.79 (2H, s), 7.85-7.80 (4H, m),7.40-7.39 (1H, m), 7.30-7.28 (4H, d), 7.20-7.16 (1H, m), 6.97-6.88 (2H,m), 6.49-6.45 (1H, d), 6.17-6.11 (1H, m), 4.20-4.16 (2H, m), 4.09-4.07(2H, m), 3.32-3.29 (4H, m), 2.90-2.49 (5H, m), 1.76-1.67 (2H, m).

LC-MS (Method 1): R_(t)=2.36 min; m/z=530 (M+H)⁺.

B. ASSESSMENT OF THE PHARMACOLOGICAL ACTIVITY

The pharmacological effect of the compounds according to the inventioncan be shown in the following assays:

B-1. Vasorelaxant Effect In Vitro:

Rabbits are anesthetized and sacrificed by intravenous injection ofthiopental sodium (about 50 mg/kg) and exsanguinated. The saphenousartery is removed and divided into rings 3 mm wide. The rings aremounted singly on in each case a pair of triangular hooks open at theend and made of 0.3 mm-thick special wire (Remanium®). Each ring isplaced under an initial tension in 5 ml organ baths with Krebs-Henseleitsolution which is at 37° C., is gassed with carbogen and has thefollowing composition: NaCl 119 mM; KCl 4.8 mM; CaCl₂×2H₂O 1 mM;MgSO₄×7H₂O 1.4 mM; KH₂PO₄ 1.2 mM; NaHCO₃ 25 mM; glucose 10 mM; bovineserum albumin 0.001%. The force of contraction is detected with StathamUC2 cells, amplified and digitized via A/D converters (DAS-1802 HC,Keithley Instruments, Munich) and recorded in parallel on chartrecorders. Contractions are induced by addition of phenylephrine.

After several (generally 4) control cycles, the substance to beinvestigated is added in each further run in increasing dosage, and theheight of the contraction achieved under the influence of the testsubstance is compared with the height of the contraction reached in thelast preceding run. The concentration necessary to reduce thecontraction reached in the preceding control by 50% is calculated fromthis (IC₅₀). The standard application volume is 5 μl. The proportion ofDMSO in the bath solution corresponds to 0.1%.

Representative results for the compounds according to the invention arelisted in Table 1:

TABLE 1 Vasorelaxant effect in vitro Example No. IC₅₀ [nM] 1 390 2 255 352 4 330 5 58 6 135B-2. Stimulation of Recombinant Soluble Guanylate Cyclase (sGC) InVitro:

Investigations on the stimulation of recombinant soluble guanylatecyclase (sGC) by the compounds according to the invention with andwithout sodium nitroprusside, and with and without the heme-dependentsGC inhibitor 1H-1,2,4-oxadiazole-(4,3a)-quinoxalin-1-one (ODQ) arecarried out by the method described in detail in the followingreference: M. Hoenicka, E. M. Becker, H. Apeler, T. Sirichoke, H.Schroeder, R. Gerzer and J.-P. Stasch, “Purified soluble guanylylcyclase expressed in a baculovirus/Sf9 system: Stimulation by YC-1,nitric oxide, and carbon oxide”, J. Mol. Med. 77 (1999), 14-23. Theheme-free guanylate cyclase is obtained by adding Tween 20 to the samplebuffer (0.5% in the final concentration).

The activation of sGC by a test substance is reported as n-foldstimulation of the basal activity. The result for Example 3 is shown inTable 2:

TABLE 2 Stimulation (n-fold) of recombinant soluble guanylate cyclase(sGC) in vitro by Example 3 Concentration Heme-containing sGC of Example3 +0.1 μM +10 μM Heme-free sGC [μM] Basal DEA/NO ODQ Basal 0.0 1.0 18.53.9 1.0 0.01 6.1 23.3 35.1 9.9 0.1 11.6 34.7 98.0 35.2 1 16.0 41.6 12469.7 10 18.9 40.0 134 74.6 [DEA/NO = 2-(N,N-diethylamino)diazenolate2-oxide; ODQ = 1H-1,2,4-oxadiazole-(4,3a)-quinoxalin-1-one].

It is evident from Table 2 that stimulation both of the heme-containingand of the heme-free enzyme is achieved. Furthermore, combination ofExample 3 and 2-(N,N-diethylamino)diazenolate 2-oxide (DEA/NO), an NOdonor, shows no synergistic effect, i.e. the effect of DEA/NO is notpotentiated as would be expected with an sGC activator acting via aheme-dependent mechanism. In addition, the effect of the sGC activatoraccording to the invention is not blocked by the heme-dependentinhibitor of soluble guanylate cyclase ODQ, but is in fact increased.The results in Table 2 thus confirm the mechanism of action of thecompounds according to the invention as activators of soluble guanylatecyclase.

B-3. Action at Recombinant Guanylate Cyclase Reporter Cell Lines

The cellular action of the compounds according to the invention isdetermined using a recombinant guanylate cyclase reporter cell line, asdescribed in F. Wunder et al., Anal. Biochem. 339, 104-112 (2005).

Representative results for the compounds according to the invention arelisted in Table 3:

TABLE 3 sGC-activating activity in the CHO reporter cell in vitroExample No. MEC [nM] 1 3 2 3 3 1 4 2 5 0.55 6 3 7 1 8 1 9 1 10 3 11 <112 100 (MEC = minimum effective concentration).B-4. Radiotelemetric Measurement of Blood Pressure and Heart Rate onConscious SH Rats

A commercially available telemetry system from Data SciencesInternational DSI, USA, is employed for the measurements on conscious SHrats described below.

The system consists of 3 main components: (1) implantable transmitter,(2) receiver which is linked via a multiplexer to a (3) data acquisitioncomputer. The telemetry system makes it possible to record continuouslythe blood pressure and heart rate on conscious animals in their usualhabitat.

The investigations are carried out on adult female spontaneouslyhypertensive rats (SH rats) with a body weight of >200 g. Aftertransmitter implantation, the experimental animals are housed singly intype 3 Makrolon cages. They have free access to standard feed and water.The day/night rhythm in the experimental laboratory is changed by theroom lighting at 6.00 in the morning and at 19.00 in the evening.

The telemetry transmitters (TAM PA-C40, DSI) as employed are surgicallyimplanted under aseptic conditions in the experimental animals at least14 days before the first experimental use. The animals instrumented inthis way can be employed repeatedly after the wound has healed and theimplant has settled.

For the implantation, the fasted animals are anesthetized withpentobarbital (Nembutal, Sanofi, 50 mg/kg i.p.) and shaved anddisinfected over a large area on the side of the abdomen. After theabdominal cavity has been opened along the linea alba, the liquid-filledmeasuring catheter of the system is inserted into the descending aortain the cranial direction above the bifurcation and fastened with tissueglue (VetBonD™, 3M). The transmitter housing is fixed intraperitoneallyto the abdominal wall muscle, and layered closure of the wound isperformed. An antibiotic (Tardomyocel COMP, Bayer, 1 ml/kg s.c.) isadministered postoperatively for prophylaxis of infection.

Outline of Experiment:

The substances to be investigated are administered orally by gavage ineach case to a group of animals (n=6). The test substances are dissolvedin suitable solvent mixtures, or suspended in 0.5% strength Tylose,appropriate for an administration volume of 5 ml/kg of body weight. Asolvent-treated group of animals is employed as control.

The telemetry measuring unit is configured for 24 animals. Eachexperiment is recorded under an experiment number.

Each of the instrumented rats living in the system is assigned aseparate receiving antenna (1010 Receiver, DSI). The implantedtransmitters can be activated from outside by means of an incorporatedmagnetic switch and are switched to transmission in the run-up to theexperiment. The emitted signals can be detected online by a dataacquisition system (Dataquest™ A.R.T. for Windows, DSI) and beappropriately processed. The data are stored in each case in a filebearing the experiment number which is open for this purpose.

In the standard procedure, the following are measured for 10-secondperiods in each case: (1) systolic blood pressure (SBP), (2) diastolicblood pressure (DBP), (3) mean arterial pressure (MAP) and (4) heartrate (HR).

Measurement acquisition is repeated under computer control at 5-minuteintervals. The source data obtained as absolute value are corrected inthe diagram with the currently measured barometric pressure and storedin individual data. Further technical details are given in thedocumentation of the manufacturing company (DSI).

The test substances are administered at 9.00 h on the day of theexperiment. Following the administration, the parameters described aboveare measured over 24 hours. After the end of the experiment, theacquired individual data are sorted using the analysis software(Dataquest™ A.R.T. Analysis). The void value is assumed to be the time 2hours before administration of the substance, so that the selected dataset includes the period from 7.00 h on the day of the experiment to 9.00h on the following day.

The data are smoothed over a presettable time by determination of theaverage (15-minute average, 30-minute average) and transferred as textfile to a storage medium. The measurements presorted and compressed inthis way are transferred into Excel templates and tabulated.

C. EXEMPLARY EMBODIMENTS OF PHARMACEUTICAL COMPOSITIONS

The compounds according to the invention can be converted intopharmaceutical preparations in the following ways:

Tablet:

Composition:

100 mg of the compound according to the invention, 50 mg of lactose(monohydrate), 50 mg of maize starch (native), 10 mg ofpolyvinylpyrrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2mg of magnesium stearate.

Tablet weight 212 mg, diameter 8 mm, radius of curvature 12 mm

Production:

A mixture of compound according to the invention, lactose and starch isgranulated with a 5% strength solution (m/m) of the PVP in water. Thegranules are dried and mixed with the magnesium stearate for 5 minutes.This mixture is compressed in a conventional tablet press (see above forformat of the tablet). A guideline compressive force for the compressionis 15 kN.

Suspension which can be Administered Orally:

Composition:

1000 mg of the compound according to the invention, 1000 mg of ethanol(96%), 400 mg of Rhodigel® (xanthan gum from FMC, Pennsylvania, USA) and99 g of water.

10 ml of oral suspension correspond to a single dose of 100 mg of thecompound according to the invention.

Production:

The Rhodigel is suspended in ethanol, and the compound according to theinvention is added to the suspension. The water is added while stirring.The mixture is stirred for about 6 h until the swelling of the Rhodigelis complete.

Solution which can be Administered Orally:

Composition:

500 mg of the compound according to the invention, 2.5 g of polysorbateand 97 g of polyethylene glycol 400.20 g of oral solution correspond toa single dose of 100 mg of the compound according to the invention.

Production:

The compound according to the invention is suspended in the mixture ofpolyethylene glycol and polysorbate with stirring. The stirring processis continued until the compound according to the invention hascompletely dissolved.

I.V.-Solution:

The compound according to the invention is dissolved in a concentrationbelow the saturation solubility in a physiologically tolerated solvent(e.g. isotonic saline, 5% glucose solution and/or 30% PEG 400 solution).The solution is sterilized by filtration and used to fill sterile andpyrogen-free injection containers.

1. A compound of the formula (I)

in which A represents a group of the formula 1

 in which * represents the point of attachment to group E, R⁴ represents(C₁-C₆)-alkyl or phenyl, x represents the number 0, 1 or 2, where if thesubstituent R⁴ occurs twice, its meanings may be identical or different,and y represents the number 2, 3 or 4, where a CH₂ group may be replacedby —O— or >N—R^(4A) in which R^(4A) is hydrogen, (C₁-C₆)-alkyl orphenyl, E represents (C₂-C₆)-alkanediyl, (C₂-C₆)-alkenediyl or(C₂-C₆)-alkynediyl, each of which may be mono- or polysubstituted byfluorine, m represents the number 1 or 2, R¹, R² and R³ independently ofone another represent a substituent selected from the group consistingof halogen, (C₁-C₆)-alkyl, trifluoromethyl, (C₁-C₆)-alkoxy,trifluoromethoxy, cyano and nitro, and n, o and p independently of oneanother each represent the number 0, 1 or 2, where, if R¹, R² or R³ ispresent more than once, their meanings may in each case be identical ofdifferent, or a salt thereof.
 2. The compound of the formula (I) asclaimed in claim 1, in which A represents a group of the formula

 in which * represents the point of attachment to group E, R⁴ represents(C₁-C₄)-alkyl or phenyl, x represents the number 0, 1 or 2, where if thesubstituent R⁴ occurs twice, its meanings may be identical or different,and y represents the number 2 or 3, where a CH₂ group may be replaced by—O— or >N—R^(4A) in which R^(4A) represents (C₁-C₄)-alkyl or phenyl, Erepresents (C₂-C₆)-alkanediyl or (C₂-C₆)-alkenediyl, m represents thenumber 1 or 2, R¹ represents a substituent selected from the groupconsisting of fluorine, chlorine, bromine, methyl, trifluoromethyl,methoxy and trifluoromethoxy, R² and R³ each represent fluorine, and n,o and p independently of one another each represent the number 0 or 1,or a salt thereof.
 3. A compound of the formula (I-A)

in which A represents a group of the formula

in which * represents the point of attachment to group E, E represents1,2-ethylene, 1,3-propylene, 1,4-butylene or 1,5-pentylene, m representsthe number 1 or 2, and R¹ represents hydrogen or fluorine, or a saltthereof.
 4. The compound of the formula (I-A) as claimed in claim 3, inwhich A represents a group of the formula

 in which * represents the point of attachment to group E, E represents1,2-ethylene, 1,3-propylene or 1,4-butylene, m represents the number 1or 2, and R¹ represents hydrogen or fluorine, or a salt thereof.
 5. Aprocess for preparing a compound of the formula (I) or (I-A) as definedin claim 1, wherein the compounds of the formula (II)

in which R², R³, m, o and p each have the meanings given in claim 1 andT¹ and T² are identical or different and represent(C₁-C₄)-alkoxycarbonyl, are either [A] converted in an inert solvent inthe presence of a base with a compound of the formula (III-A)

in which A, E, R¹ and n each have the meanings given in claim 1 and Lrepresents phenyl or o-, m- or p-tolyl and X represents halide ortosylate, into compounds of the formula (IV-A)

in which A, E, R¹, R², R³, m, n, o, p, T¹ and T² each have the meaningsgiven above, or [B] converted in an inert solvent in the presence of abase with a compound of the formula (III-B)

in which R¹, n, L and X each have the meanings given above, initiallyinto compounds of the formula (IV-B)

in which R¹, R², R³, m, n, o, p, T¹ and T² each have the meanings givenabove, and these are then alkylated in an inert solvent in the presenceof a base with a compound of the formula (V)A-E-Q  (V), in which A and E have the meanings given in claim 1 and Qrepresents a leaving group, such as, for example, halogen, tosylate ormesylate, to give compounds of the formula (IV-C)

in which A, E, R¹, R², R³, m, n, o, p, T¹ and T² each have the meaningsgiven above, and the resulting compounds of the formula (IV-A) or (IV-C)are converted by hydrolysis of the ester groups T¹ and T² into thedicarboxylic acids of the formula (I) and the compounds of the formula(I) are separated where appropriate by methods known to the skilledperson into their enantiomers and/or diastereomers, and/or whereappropriate reacted with the appropriate (i) solvents and/or (ii) basesor acids to give the or a salt thereof.
 6. The compound as defined inclaim 1 for the treatment of diseases.
 7. A pharmaceutical compositioncomprising a compound as defined in claim 1 in combination with one ormore inert, non-toxic, pharmaceutically suitable excipients.
 8. Thepharmaceutical composition of claim 7, further comprising one or morefurther active ingredients selected from the group consisting of organicnitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylatecyclase, agents having antithrombotic activity, agents lowering bloodpressure, and agents altering lipid metabolism.
 9. The pharmaceuticalcomposition as claimed in claim 7 for the treatment of heart failure,angina pectoris, hypertension, pulmonary hypertension, ischemias,vascular disorders, thromboembolic disorders and arteriosclerosis.
 10. Amethod for the treatment of heart failure, angina pectoris,hypertension, pulmonary hypertension, ischemias, vascular disorders,thromboembolic disorders and arteriosclerosis in humans and animals byadministration of an effective amount of at least one compound asdefined in claim
 1. 11. A method for the treatment of heart failure,angina pectoris, hypertension, pulmonary hypertension, ischemias,vascular disorders, thromboembolic disorders and arteriosclerosis inhumans and animals by administration of an effective amount of thepharmaceutical composition of claim 7.